U.S. patent number 8,293,253 [Application Number 11/259,027] was granted by the patent office on 2012-10-23 for compositions for controlled delivery of pharmaceutically active compounds.
This patent grant is currently assigned to IDEXX Laboratories, Inc.. Invention is credited to Yerramilli V. S. N. Murthy.
United States Patent |
8,293,253 |
Murthy |
October 23, 2012 |
Compositions for controlled delivery of pharmaceutically active
compounds
Abstract
The invention relates to pharmaceutical compositions that
provide sustained-release of a pharmaceutically active compound and
to methods of treating or preventing a condition in an animal by
administering the pharmaceutical compositions to the animal by
injection. When the pharmaceutical compositions are administered to
an animal by injection, they form a drug depot that releases the
pharmaceutically active compound over time. The pharmaceutical
compositions can also be administered orally.
Inventors: |
Murthy; Yerramilli V. S. N.
(Apex, NC) |
Assignee: |
IDEXX Laboratories, Inc.
(Westbrook, ME)
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Family
ID: |
36319633 |
Appl.
No.: |
11/259,027 |
Filed: |
October 27, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20060093632 A1 |
May 4, 2006 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60638178 |
Dec 23, 2004 |
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60622689 |
Oct 28, 2004 |
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Current U.S.
Class: |
424/400;
514/561 |
Current CPC
Class: |
A61K
31/7076 (20130101); A61K 31/198 (20130101); A61P
31/00 (20180101); A61K 31/7056 (20130101); A61K
31/198 (20130101); A61K 2300/00 (20130101); A61K
31/7056 (20130101); A61K 2300/00 (20130101); A61K
31/7076 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A01N 37/12 (20060101) |
Field of
Search: |
;424/468 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 03/034988 |
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May 2003 |
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WO |
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WO2004089239 |
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Oct 2004 |
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WO |
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WO2005000241 |
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Jan 2005 |
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WO |
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Primary Examiner: Blanchard; David J
Assistant Examiner: Bredefeld; Rachael E
Attorney, Agent or Firm: Haynes and Boone, LLP
Parent Case Text
1. CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. provisional application
No. 60/638,178, filed Dec. 23, 2004, and U.S. provisional
application No. 60/622,689, filed Oct. 28, 2004, the contents of
which are expressly incorporated herein.
Claims
What is claimed is:
1. An injection composition comprising (i) a salt formed between
(a) an amino acid ester of formula I: ##STR00006## wherein R is the
amino acid side chain; and R.sub.1 is a C.sub.1 to C.sub.22
hydrocarbon group or amino acid amide of formula (II): ##STR00007##
wherein R is the amino acid side chain; R.sub.3 is a C.sub.1 to
C.sub.22 hydrocarbon group; and R.sub.4 is hydrogen or a C.sub.1 to
C.sub.22 hydrocarbon group, and (b) an acidic pharmaceutically
active compound; and (ii) a pharmaceutically acceptable organic
solvent; formulated to be administered to an animal by injection,
wherein the composition is substantially free of water, the
composition is injectable and forms a precipitate when injected
into water, and the composition, when administered to an animal by
injection, forms a depot that releases the pharmaceutically active
compound over time.
2. The composition of claim 1, wherein the amino acid ester or
amino acid amide is an ester or amide of an amino acid selected
from the group consisting of glycine, alanine, valine, leucine,
isoleucine, phenylalanine, asparagine, glutamine, tryptophane,
proline, serine, threonine, tyrosine, hydroxyproline, cysteine,
methionine, aspartic acid, glutamic acid, lysine, arginine, and
histidine.
3. The composition of claim 1, wherein the amino acid ester is
obtained by esterifying an amino acid with a straight or branched
chain, saturated or unsaturated alkyl alcohol.
4. The composition of claim 3, wherein the alkyl alcohol is a
C.sub.1 to C.sub.22 alcohol.
5. The composition of claim 4, wherein C.sub.1 to C.sub.22 alcohol
is selected from the group consisting of, methanol, ethanol,
propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol,
decanol, undecanol, dodecanol, tridecanol, tetradecanol,
pentadecanol, hexadecanol, heptadecanol, octadecanol, allyl
alcohol, cyclopentanol, cyclohexanol, cis-9-hexadecenanol,
cis-9-octadecenanol, cis, cis-9,12-octadecenanol, and cis, cis,
cis-9, 12,15-octadecatrienanol.
6. The composition of claim 1, wherein the acidic pharmaceutically
active compound is selected from the group consisting of aspirin,
flunixin, diclofenac, naproxen, ketoprofen, carprofen, and
ibuprofen.
7. The composition of claim 1, wherein acidic pharmaceutically
active compound is a phosphorylated nucleotide.
8. The composition of claim 7, wherein the nucleotide is
adefovir.
9. The composition of claim 1, wherein the solvent is selected from
the group consisting of pyrrolidone, N-methyl-2-pyrrolidone,
polyethylene glycol, propylene glycol, glycerol formal, isosorbid
dimethyl ether, ethanol, dimethyl sulfoxide, tetraglycol,
tetrahydrofurfuryl alcohol, triacetin, propylene carbonate,
dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, and
combinations thereof.
10. The composition of claim 1, wherein the molar ratio of acidic
groups on the acidic pharmaceutically active compound to the amino
acid ester ranges from about 1.5:1 to 1:1.
11. The composition of claim 1, wherein the molar ratio of acidic
groups on the acidic pharmaceutically active compound to the amino
acid ester is about 1:1.
12. The composition of claim 1, wherein the combined amount of the
acidic pharmaceutically active compound and the amino acid ester is
present in an amount ranging from about 1 to 90 percent by weight
of the pharmaceutical composition.
13. The composition of claim 1, wherein the combined amount of the
acidic pharmaceutically active compound and the amino acid ester is
present in an amount ranging from about 10 to 60 percent by weight
of the pharmaceutical composition.
14. The composition of claim 1, wherein the pharmaceutically active
compound is flunixin and the amino acid ester is tryptophan
octanoate or tryptophan butanoate.
15. The composition of claim 1, wherein the pharmaceutically
acceptable organic solvent is about 5% propylene glycol in glycerol
formal.
16. The composition of claim 1, comprising an amino acid ester,
wherein R.sub.1 is a C.sub.10-C.sub.18 hydrocarbon group.
17. The composition of claim 1, comprising an amino acid amide of
formula (II).
Description
2. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT
Not Applicable.
3. INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT
DISC
Not Applicable.
4. FIELD OF THE INVENTION
The invention relates to sustained-release pharmaceutical
compositions and to methods of administering pharmaceutically
active compounds to an animal using the sustained-release
pharmaceutical compositions.
5. BACKGROUND OF THE INVENTION
It is often desirable to administer drugs using controlled- or
sustained-release formulations that can maintain therapeutic blood
levels of the drug over extended periods of time. These controlled
release formulations reduce the frequency of dosing, for enhanced
convenience and compliance, and also reduce the severity and
frequency of side effects. By maintaining substantially constant
blood levels and avoiding blood level fluctuations of the drug,
such as are associated with conventional immediate release
formulations that are administered several times a day, controlled-
or sustained-release formulations can provide a better therapeutic
profile than is obtainable with conventional immediate release
formulations.
Known methods for controlled- or sustained-drug release include
implanted devices, such as osmotic pumps, and drug dispersed in a
biocompatible polymer matrix, which can be implanted, administered
orally, or injected. Examples of biocompatible polymers used in
such applications include poly(lactic acid) and poly(lactic
acid-co-glycolic acid). The polymer typically undergoes slow
hydrolysis in vivo to continually release the entrapped drug over
time. The polymer degradation products are non-toxic and absorbed
or metabolized by the body. For example, when the biocompatible
polymer is poly(lactic acid) or poly(lactic acid-co-glycolic acid),
the degradation products are the parent acids, lactic acid and
glycolic acid, which are absorbed by the body.
U.S. Pat. Nos. 6,887,487 and 6,946,137 disclose compositions of a
salt of a pharmacologically active compound and a lipophilic
counterion and a pharmaceutically acceptable water soluble solvent
that are combined together to provide an injectable composition.
When injected into an animal at least a part of the composition
precipitates to form a depot that slowly releases the
pharmacologically active compound over time.
U.S. patent application no. US 2004/0220264 discloses compositions,
methods of making the compositions, and uses of compositions that
include a molecular complex between an acidic pharmaceutical drug
and a functional substance. The functional substance can be an
alkaline amino acid, an amino acid amide, an amino acid ester, or a
related amino acid. The compositions are allegedly useful for
delivering the drug into cutaneous tissue.
U.S. patent application no. US 2004/0197408 discloses formulations
of a diblock copolymer having a hydrophobic block and hydrophilic
block, an additive selected from an amino acid, and an
oligopeptide. The formulations, when admixed with water, form drug
delivery vehicles in micellar form.
There remains a need in the art, however, for drug containing
pharmaceutical compositions, suitable for injection or
implantation, wherein the formulation provides controlled- or
sustained-release of the drug.
Citation of any reference in Section 5 of this application is not
to be construed that such reference is prior art to the present
application.
6. SUMMARY OF THE INVENTION
The invention relates to a pharmaceutical composition comprising
(i) an amino acid ester or an amino acid amide, (ii) an acidic
pharmaceutically active compound, and (iii) a pharmaceutically
acceptable organic solvent, wherein the pharmaceutical composition
is injectable and forms a precipitate when injected into water. In
one embodiment, the pharmaceutical composition comprises an amino
acid ester. In one embodiment, the pharmaceutical composition
comprises an amino acid amide.
The invention further relates to a pharmaceutical composition
comprising (i) an amino acid ester or amino acid amide, (ii) a
carboxylic acid, (iii) a neutral pharmaceutically active compound
or a pharmaceutically acceptable salt of a pharmaceutically active
compound, and (iv) a pharmaceutically acceptable organic solvent,
wherein the pharmaceutical composition is injectable and forms a
precipitate when injected into water. In one embodiment, the
pharmaceutical composition comprises an amino acid ester. In one
embodiment, the pharmaceutical composition comprises an amino acid
amide.
The invention further relates to a pharmaceutical composition
comprising (i) an N-acyl amino acid, (ii) a basic pharmaceutically
active compound, and (iii) a pharmaceutically acceptable organic
solvent, wherein the pharmaceutical composition is injectable and
forms a precipitate when injected into water.
The invention further relates to methods of treating a condition in
an animal comprising administering to an animal in need thereof a
pharmaceutical composition of the invention.
7. BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the percent of flunixin released as a function of time
for various flunixin formulations. (.tangle-solidup.) represents
the percent of flunixin released from a composition containing a
salt of flunixin and tryptophan octanoate, (.box-solid.) represents
the percent of flunixin released from a composition containing a
salt of flunixin and tryptophan butanoate, and (.diamond-solid.)
represents the percent of flunixin released from a composition
containing free flunixin dissolved in N-methylpyrrolidone.
FIG. 2 depicts the average serum concentration of flunixin as a
function of time for two dogs administered Banamine.RTM. at a dose
of 8 mg/kg.
FIG. 3 depicts the average serum concentration of flunixin as a
function of time for four dogs administered a composition of the
invention containing a salt of flunixin and tryptophan octanoate in
propylene glycol and glycerol formal, prepared as described in
Example 9.2, at a dose of 8 mg/kg.
8. DETAILED DESCRIPTION OF THE INVENTION
The invention relates to pharmaceutical compositions for
administering pharmaceutically active compounds. The compositions
provide sustained- or controlled-release of the pharmaceutically
active compound. The invention further relates to methods of
treating a condition in an animal comprising administering to an
animal in need thereof a pharmaceutical composition of the
invention.
The invention relates to a pharmaceutical composition comprising
(i) an amino acid ester or an amino acid amide and (ii) an acidic
pharmaceutically active compound. In one embodiment, the
pharmaceutical composition comprises an amino acid ester. In one
embodiment, the pharmaceutical composition comprises an amino acid
amide. In one embodiment, the pharmaceutical composition is a
solid.
In one embodiment, the pharmaceutical composition further comprises
a pharmaceutically acceptable organic solvent. Accordingly, the
invention further relates to a pharmaceutical composition
comprising (i) an amino acid ester or an amino acid amide, (ii) an
acidic pharmaceutically active compound, and (iii) a
pharmaceutically acceptable organic solvent. In one embodiment, the
pharmaceutical composition comprises an amino acid ester. In one
embodiment, the pharmaceutical composition comprises an amino acid
amide. In one embodiment, the pharmaceutical composition further
comprising a pharmaceutically acceptable organic solvent comprises
a suspension of solid particles in the pharmaceutically acceptable
organic solvent. In one embodiment, the pharmaceutical composition
further comprising a pharmaceutically acceptable organic solvent is
injectable and forms a precipitate when injected into water.
The invention further relates to a pharmaceutical composition
comprising (i) an amino acid ester or amino acid amide, (ii) a
carboxylic acid, and (iii) a neutral pharmaceutically active
compound or a pharmaceutically acceptable salt of a
pharmaceutically active compound. In one embodiment, the
pharmaceutical composition comprises an amino acid ester. In one
embodiment, the pharmaceutical composition comprises an amino acid
amide. In one embodiment, the pharmaceutical composition is a
solid.
In one embodiment, the pharmaceutical composition further comprises
a pharmaceutically acceptable organic solvent. Accordingly, the
invention further relates to a pharmaceutical composition
comprising (i) an amino acid ester or amino acid amide, (ii) a
carboxylic acid, (iii) a neutral pharmaceutically active compound
or a pharmaceutically acceptable salt of a pharmaceutically active
compound, and (iv) a pharmaceutically acceptable organic solvent.
In one embodiment, the pharmaceutical composition comprises an
amino acid ester. In one embodiment, the pharmaceutical composition
comprises an amino acid amide. In one embodiment, the
pharmaceutical composition further comprising a pharmaceutically
acceptable organic solvent comprises a suspension of solid
particles in the pharmaceutically acceptable organic solvent. In
one embodiment, the pharmaceutical composition further comprising a
pharmaceutically acceptable organic solvent is injectable and forms
a precipitate when injected into water.
The invention further relates to a pharmaceutical composition
comprising (i) an N-acyl amino acid and (ii) a basic
pharmaceutically active compound. In one embodiment, the
pharmaceutical composition is a solid.
In one embodiment, the pharmaceutical composition further comprises
a pharmaceutically acceptable organic solvent. Accordingly, the
invention further relates to a pharmaceutical composition
comprising (i) an N-acyl amino acid, (ii) a basic pharmaceutically
active compound, and (iii) a pharmaceutically acceptable organic
solvent. In one embodiment, the pharmaceutical composition further
comprising a pharmaceutically acceptable organic solvent comprises
a suspension of solid particles in the pharmaceutically acceptable
organic solvent. In one embodiment, the pharmaceutical composition
further comprising a pharmaceutically acceptable organic solvent is
injectable and forms a precipitate when injected into water.
8.1 Definitions
As used herein, the following terms have the following meaning:
"C.sub.1-C.sub.22 hydrocarbon group" means a straight or branched,
saturated or unsaturated, cyclic or non-cyclic, aromatic or
non-aromatic, carbocyclic or heterocyclic group having from 1 to 22
carbon atoms. Similarly, "C.sub.1-C.sub.21 hydrocarbon group,"
"C.sub.1-C.sub.18 hydrocarbon group," "C.sub.6-C.sub.18 hydrocarbon
group," "C.sub.8-C.sub.18 hydrocarbon group," and a
"C.sub.10-C.sub.18 hydrocarbon group" means a straight or branched,
saturated or unsaturated, cyclic or non-cyclic, aromatic or
non-aromatic, carbocyclic or heterocyclic group having from 1 to 21
carbon atoms, from 1 to 18 carbon atoms, from 6 to 18 carbon atoms,
from 8 to 18 carbon atoms, and from 10 to 18 carbon atoms,
respectively. Accordingly, the phrase "an acyl group of formula
--C(O)--R.sub.1, wherein R.sub.1 is a C.sub.1 to C.sub.21 group
means an acyl group of formula --C(O)--R.sub.1, wherein R.sub.1 is
a straight or branched, saturated or unsaturated, cyclic or
non-cyclic, aromatic or non-aromatic, carbocyclic or heterocyclic
hydrocarbon group having from 1 to 21 carbon atoms. Representative
acyl groups of formula --C(O)--R.sub.1, wherein R.sub.1 is an
unsubstituted C.sub.1 to C.sub.21 group include, but are not
limited to, acetyl, propionyl, butanoyl, hexanoyl, caproyl,
laurolyl, myristoyl, palmitoyl, stearoyl, palmioleoyl, oleoyl,
linoleoyl, linolenoyl, and benzoyl.
The term "salt," as used herein, means two compounds that are not
covalently bound but are chemically bound by ionic
interactions.
The term "pharmaceutically acceptable organic solvent," as used
herein, means an organic solvent that when administered to an
animal does not have undue adverse effects such as excessive
toxicity, irritation, or allergic response commensurate with a
reasonable benefit/risk ratio. Preferably, the pharmaceutically
acceptable organic solvent is a solvent that is generally
recognized as safe ("GRAS") by the United States Food and Drug
Administration ("FDA").
The term "water miscible organic solvent," as used herein, means an
organic solvent that is capable of mixing with water in any ratio
without separating into two phases.
The term "water soluble organic solvent," as used herein, means an
organic solvent that has a significant level of solubility in
water. Typically, a water soluble organic solvent is soluble in
water in an amount of at least about 5 percent by weight,
preferably at least about 10 percent by weight, more preferably at
least about 20 percent by weight, and most preferably at least
about 50 percent by weight. For example, triacetin is considered a
water soluble solvent since it is soluble in water at a ratio of
about 1:14.
The phrase "forms a precipitate," as used herein, means that the
pharmaceutical composition forms a precipitate, or solid, when
injected into water or into a physiological (in vivo) environment.
A precipitate is an insoluble solid formed in solution at room
temperature in vitro or in a physiological (in vivo) environment.
The precipitate can take many forms such as, for example, a solid,
a crystal, a gummy mass, or a gel. Preferably, the precipitate is a
gummy mass or a gel. A composition of the invention forms a
precipitate in water when at least 10% of the composition is
retained on a 0.22 .mu.m filter when the composition is mixed with
water and filtered at 98.degree. F. Typically, to form the
precipitate, about 1 mL of the pharmaceutical composition is
injected into about 5 mL of water.
The term "fatty acid," as used herein means a carboxylic acid of
formula R--C(O)OH, wherein R a is C.sub.6-C.sub.22 linear or
branched, saturated or unsaturated, hydrocarbon group.
Representative fatty acids include, but are not limited to, caproic
acid, lauric acid, myristic acid, palmitic acid, stearic acid,
palmic acid, oleic acid, linoleic acid, and linolenic acid.
The term "fluoroquinolone," as used herein, means any compound
having the basic structure:
##STR00001## wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 can be
a variety of functional groups and X can be carbon, which may be
substituted or unsubstituted, or nitrogen. One skilled in the art
would readily recognize fluoroquinolones useful in the compositions
and methods of the invention. Typically, the fluoroquinolones are
useful as antibiotics but they may also be used to treat other
conditions (for example, nephrotic syndromes).
The phrase "injectable" or "injectable composition," as used
herein, means a composition that can be drawn into a syringe and
injected subcutaneously, intraperitoneally, or intramuscularly into
an animal without causing adverse effects due to the presence of
solid material in the composition. Solid materials include, but are
not limited to, crystals, gummy masses, and gels. Typically, a
formulation or composition is considered to be injectable when no
more than 10%, preferably no more than 5%, more preferably no more
than 2%, and most preferably no more than 1% of the formulation is
retained on a 0.22 .mu.m filter when the formulation is filtered
through the filter at 98.degree. F.
The term "suspension," as used herein, means solid particles that
are evenly dispersed in a solvent, which can be aqueous or
non-aqueous. In one embodiment, the particles have an average
particle size of less than about 100 .mu.m determined using a
particle size analyzer such as commercially available from
Microtrac Inc. of Montgomeryville, Pa.
The term "animal," as used herein, includes, but is not limited to,
humans, canines, felines, equines, bovines, ovines, porcines,
amphibians, reptiles, and avians. Representative animals include,
but are not limited to a cow, a horse, a sheep, a pig, an ungulate,
a chimpanzee, a monkey, a baboon, a chicken, a turkey, a mouse, a
rabbit, a rat, a guinea pig, a dog, a cat, and a human. In one
embodiment, the animal is a mammal. In one embodiment, the animal
is a human. In one embodiment, the animal is a canine, a feline, an
equine, a bovine, an ovine, or a porcine.
The term "pharmaceutically active compound," as used herein, means
a compound that causes a pharmacological effect in an animal.
Typically, the pharmacological effect is treating or preventing a
condition in an animal.
The term "condition," as used herein means an interruption,
cessation, or disorder of a bodily function, system, or organ.
Representative conditions include, but are not limited to,
infections such as bacterial, viral, fungal and, parasitic
infections; diseases such as cancer; inflammation; diabetes; and
organ failure.
The term "effective amount," as used herein, means an amount
sufficient to treat or prevent a condition in an animal.
The phrase "treating," "treatment of," and the like includes the
amelioration or cessation of a specified condition.
The phrase "preventing," "prevention of," and the like include the
avoidance of the onset of a condition.
The phrase "drug depot," as used herein means a precipitate that
includes the pharmaceutically active compound formed within the
body of a treated animal that releases a pharmaceutically effective
amount of the pharmaceutically active compound over time.
The phrase "neutral pharmaceutically active compound," as used
herein means a pharmaceutically active compound that has no net
charge. Neutral pharmaceutically active compounds include
zwitterions.
The phrase "acidic pharmaceutically active compound," as used
herein means a pharmaceutically active compound that has an acidic
functional group, i.e., a group that is capable of donating a
proton to a basic functional group such as an amine group.
Representative acidic functional group include, but are not limited
to --COOH (i.e., carboxylic acid groups), --S(O).sub.2--OH (i.e.,
sulfonic acid groups), --OP(O)(OR)(OH), --O(P)(OH).sub.2,
--P(O)(OR)(OH), --(P)(OH).sub.2), --OP(O)(R)(OH), and
--P(O)(R)(OH), wherein R is a hydrocarbon group that can optionally
be substituted.
The phrase "basic pharmaceutically active compound," as used herein
means a pharmaceutically active compound that has a basic
functional group, i.e., a group that is capable of accepting a
proton from an acidic functional group such as a carboxylic acid
group. A representative basic functional group is an amine
group.
The phrase "pharmaceutically acceptable salt," as used herein, is a
salt formed from an acid and a basic group of a pharmaceutically
active compounds. Illustrative salts include, but are not limited,
to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,
nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,
lactate, salicylate, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term
"pharmaceutically acceptable salt" also refers to a salt prepared
from a pharmaceutically active compound having an acidic functional
group, such as a carboxylic acid functional group, and a
pharmaceutically acceptable inorganic or organic base. Suitable
bases include, but are not limited to, hydroxides of alkali metals
such as sodium, potassium, and lithium; hydroxides of alkaline
earth metal such as calcium and magnesium; hydroxides of other
metals, such as aluminum and zinc; ammonia, and organic amines,
such as unsubstituted or hydroxy-substituted mono-, di-, or
trialkylamines; dicyclohexylamine; tributyl amine; pyridine;
N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-,
or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or
tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy
lower alkyl)-amines, such as N,N,-dimethyl-N-(2-hydroxyethyl)amine,
or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids
such as arginine, lysine, and the like.
The phrase "substantially free of," as used herein, means less than
about 2 percent by weight, preferably less than about 1 percent by
weight, more preferably less than about 0.5 percent by weight, and
most preferably less than about 0.2 percent by weight. For example,
the phrase "a pharmaceutical composition substantially free of
water" means that the amount of water in the pharmaceutical
composition is less than about 2 percent by weight of the
pharmaceutical composition, preferably less than about 1 percent by
weight of the pharmaceutical composition, more preferably less than
about 0.5 percent by weight of the pharmaceutical composition, and
most preferably less than about 0.2 percent by weight of the
pharmaceutical composition.
The term "somatotropin," as used herein, means a polypeptide that
has biological activity and chemical structure substantially
similar to that of a somatotropin produced in the pituitary gland
of an animal. Such somatotropins include natural somatotropins
produced by pituitary somatotropic cells and somatotropins
expressed by genetically transformed microorganisms such as E.
coli, other bacteria, or yeast. Such microorganism produced
somatotropins may have an amino acid sequence identical to the
natural somatotropin or can be analogs having one or more
variations in amino acid sequence which can provide enhanced
biological activity or some other advantage. Somatotropins include
hormones useful for enhancing lean-to-fat ratio, feed efficiency,
and milk production in various mammalian species including, but not
limited to, cattle (e.g., dairy cows), sheep, goats and swine.
Representative somatotropins include, but are not limited to,
natural or microbially expressed bovine, ovine, and porcine
somatotropins; bovine, porcine, or other animal prolactins; growth
hormone releasing factors; placental lactogens; and insulin-like
growth factors.
8.2 The Amino Acid Esters
The amino acid esters can be any ester of any amino acid, i.e., an
amino acid wherein the carboxylic acid group of the amino acid is
esterified with a C.sub.1-C.sub.22 alcohol. Accordingly, the amino
acid esters have the general formula (I):
##STR00002## wherein R is the amino acid side chain; and R.sub.1 is
a C.sub.1 to C.sub.22 hydrocarbon group.
As one of ordinary skill in the art would readily know, a wide
variety of groups are possible for the amino acid side, R. For
example, the amino acid side can be a hydrocarbon group that can be
optionally substituted. Suitable substituents include, but are not
limited to, halo, nitro, cyano, thiol, amino, hydroxy, carboxylic
acid, sulfonic acid, aromatic group, and aromatic or non-aromatic
heterocyclic group. Preferably the amino acid side chain is a
C.sub.1-C.sub.10 straight or branched chain hydrocarbon, optionally
substituted with a thiol, amino, hydroxy, carboxylic acid, aromatic
group, or aromatic or non-aromatic heterocyclic group; an aromatic
group, or an aromatic or non-aromatic heterocyclic group.
The amino acid ester can be an ester of a naturally occurring amino
acid or a synthetically prepared amino acid. The amino acid can be
a D-amino acid or an L-amino acid. Preferably, the amino acid ester
is the ester of a naturally occurring amino acid. More, preferably,
the amino acid ester is an ester of an amino acid selected from
glycine, alanine, valine, leucine, isoleucine, phenylalanine,
asparagine, glutamine, tryptophane, proline, serine, threonine,
tyrosine, hydroxyproline, cysteine, methionine, aspartic acid,
glutamic acid, lysine, arginine, and histidine.
The hydrocarbon group, R.sub.1, can be any C.sub.1 to C.sub.22
hydrocarbon group. Representative C.sub.1 to C.sub.22 hydrocarbon
groups include, but are not limited to, methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,
octadecyl, allyl, cyclopentyl, cyclohexyl, cis-9-hexadecenyl,
cis-9-octadecenyl, cis, cis-9,12-octadecenyl, and cis, cis, cis-9,
12, 15-octadecatrienyl.
In one embodiment, R.sub.1 is a straight or branched chain,
saturated or unsaturated alkyl group.
In one embodiment, R.sub.1 is a straight chain alkyl group.
In one embodiment, R.sub.1 is a branched chain alkyl group.
In one embodiment, R.sub.1 is a saturated alkyl group.
In one embodiment, R.sub.1 is an unsaturated alkyl group.
In one embodiment, R.sub.1 is a straight chain, saturated alkyl
group.
In one embodiment, R.sub.1 is a straight chain, unsaturated alkyl
group.
In one embodiment, R.sub.1 is a C.sub.6-C.sub.18 hydrocarbon
group.
In one embodiment, R.sub.1 is a C.sub.8-C.sub.18 hydrocarbon
group.
In one embodiment, R.sub.1 is a C.sub.10-C.sub.18 hydrocarbon
group.
In one embodiment, R.sub.1 is a C.sub.6-C.sub.18 straight chain
alkyl group.
In one embodiment, R.sub.1 is a C.sub.6-C.sub.18 branched chain
alkyl group.
In one embodiment, R.sub.1 is a C.sub.6-C.sub.18 saturated alkyl
group.
In one embodiment, R.sub.1 is a C.sub.6-C.sub.18 unsaturated alkyl
group.
In one embodiment, R.sub.1 is a C.sub.8-C.sub.18 straight chain
alkyl group.
In one embodiment, R.sub.1 is a C.sub.8-C.sub.18 branched chain
alkyl group.
In one embodiment, R.sub.1 is a C.sub.8-C.sub.18 saturated alkyl
group.
In one embodiment, R.sub.1 is a C.sub.8-C.sub.18 unsaturated alkyl
group.
In one embodiment, R.sub.1 is a C.sub.10-C.sub.18 straight chain
alkyl group.
In one embodiment, R.sub.1 is a C.sub.10-C.sub.18 branched chain
alkyl group.
In one embodiment, R.sub.1 is a C.sub.10-C.sub.18 saturated alkyl
group.
In one embodiment, R.sub.1 is a C.sub.10-C.sub.18 unsaturated alkyl
group.
The amino acid esters can be obtained by esterifying an amino acid
with an alcohol of formula R.sub.1--OH using methods well known to
those skilled in the art such as those described in J. March,
Advanced Organic Chemistry, Reaction Mechanisms and Structure,
4.sup.th ed. John Wiley & Sons, NY, 1992, pp. 393-400. The
amino acids and alcohols of formula R.sub.1--OH are commercially
available or can be prepared by methods well known to those skilled
in the art. When esterifying the amino acid with the alcohol of
formula R.sub.1--OH, it may be necessary to protect some other
functional group of the amino acid or the alcohol with a protecting
group that is subsequently removed after the esterification
reaction. One of ordinary skill in the art would readily know what
functional groups would need to be protected before esterifying the
amino acid with the alcohol of formula R.sub.1--OH. Suitable
protecting groups are known to those skilled in the art such as
those described in T. W. Greene, et al. Protective Groups in
Organic Synthesis, 3.sup.rd ed. (1999).
8.3 The Amino Acid Amides
The amino acid amides can be any amide of any amino acid, i.e., an
amino acid wherein the carboxylic acid group of the amino acid is
reacted with a C.sub.1-C.sub.22 amine to provide an amide.
Accordingly, the amino acid amides have the general formula
(I):
##STR00003## wherein R is the amino acid side chain; R.sub.3 is a
C.sub.1 to C.sub.22 hydrocarbon group; and R.sub.4 is hydrogen or a
C.sub.1 to C.sub.22 hydrocarbon group.
As one of ordinary skill in the art would readily know, a wide
variety of groups are possible for the amino acid side, R. For
example, the amino acid side can be a hydrocarbon group that can be
optionally substituted. Suitable substituents include, but are not
limited to, halo, nitro, cyano, thiol, amino, hydroxy, carboxylic
acid, sulfonic acid, aromatic group, and aromatic or non-aromatic
heterocyclic group. Preferably the amino acid side chain is a
C.sub.1-C.sub.10 straight or branched chain hydrocarbon, optionally
substituted with a thiol, amino, hydroxy, carboxylic acid, aromatic
group, or aromatic or non-aromatic heterocyclic group; an aromatic
group, or an aromatic or non-aromatic heterocyclic group.
The amino acid amide can be an amide of a naturally occurring amino
acid or a synthetically prepared amino acid. The amino acid can be
a D-amino acid or an L-amino acid. Preferably, the amino acid ester
is the ester of a naturally occurring amino acid. More, preferably,
the amino acid ester is an ester of an amino acid selected from
glycine, alanine, valine, leusine, isoleucine, phenylalanine,
asparagine, glutamine, tryptophane, proline, serine, threonine,
tyrosine, hydroxyproline, cysteine, methionine, aspartic acid,
glutamic acid, lysine, arginine, and histidine.
The R.sub.3 group can be any C.sub.1 to C.sub.22 hydrocarbon group.
The R.sub.4 group can be hydrogen or any C.sub.1 to C.sub.22
hydrocarbon group. Representative C.sub.1 to C.sub.22 hydrocarbon
groups include, but are not limited to, methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,
dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,
octadecyl, allyl, cyclopentyl, cyclohexyl, cis-9-hexadecenyl,
cis-9-octadecenyl, cis, cis-9,12-octadecenyl, and cis, cis,
cis-9,12,15-octadecatrienyl.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a straight or
branched chain, saturated or unsaturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a straight
chain alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a branched
chain alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a saturated
alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is an
unsaturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a straight
chain, saturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a straight
chain, unsaturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.6-C.sub.18 hydrocarbon group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.6-C.sub.18 straight chain alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.6-C.sub.18 branched chain alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.6-C.sub.18 saturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is an
C.sub.6-C.sub.18 unsaturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.8-C.sub.18 hydrocarbon group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.8-C.sub.18 straight chain alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.8-C.sub.18 branched chain alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.8-C.sub.18 saturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is an
C.sub.8-C.sub.18 unsaturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.10-C.sub.18 hydrocarbon group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.10-C.sub.18 straight chain alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.10-C.sub.18 branched chain alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is a
C.sub.10-C.sub.18 saturated alkyl group.
In one embodiment, R.sub.4 is hydrogen and R.sub.3 is an
C.sub.10-C.sub.18 unsaturated alkyl group.
In one embodiment, each of R.sub.3 and R.sub.4 are a straight or
branched chain, saturated or unsaturated alkyl group, wherein
R.sub.3 and R.sub.4 may be the same or different.
In one embodiment, each of R.sub.3 and R.sub.4 are a
C.sub.6-C.sub.18 hydrocarbon group, wherein R.sub.3 and R.sub.4 may
be the same or different.
In one embodiment, each of R.sub.3 and R.sub.4 are a
C.sub.8-C.sub.18 hydrocarbon group, wherein R.sub.3 and R.sub.4 may
be the same or different.
In one embodiment, each of R.sub.3 and R.sub.4 are a
C.sub.10-C.sub.18 hydrocarbon group, wherein R.sub.3 and R.sub.4
may be the same or different.
In one embodiment, the combined number of carbon atoms in R.sub.3
and R.sub.4 is at least 6. In one embodiment, the combined number
of carbon atoms in R.sub.3 and R.sub.4 is at least 8. In one
embodiment, the combined number of carbon atoms in R.sub.3 and
R.sub.4 is at least 10. In one embodiment, the combined number of
carbon atoms in R.sub.3 and R.sub.4 is at least 12.
In one embodiment, the combined number of carbon atoms in R.sub.3
and R.sub.4 ranges from about 6 to 30. In one embodiment, the
combined number of carbon atoms in R.sub.3 and R.sub.4 ranges from
about 8 to 30. In one embodiment, the combined number of carbon
atoms in R.sub.3 and R.sub.4 ranges from about 10 to 30. In one
embodiment, the combined number of carbon atoms in R.sub.3 and
R.sub.4 ranges from about 12 to 30. In one embodiment, the combined
number of carbon atoms in R.sub.3 and R.sub.4 ranges from about 6
to 22. In one embodiment, the combined number of carbon atoms in
R.sub.3 and R.sub.4 ranges from about 8 to 22. In one embodiment,
the combined number of carbon atoms in R.sub.3 and R.sub.4 ranges
from about 10 to 22. In one embodiment, the combined number of
carbon atoms in R.sub.3 and R.sub.4 ranges from about 12 to 22. In
one embodiment, the combined number of carbon atoms in R.sub.3 and
R.sub.4 ranges from about 6 to 18. In one embodiment, the combined
number of carbon atoms in R.sub.3 and R.sub.4 ranges from about 8
to 18. In one embodiment, the combined number of carbon atoms in
R.sub.3 and R.sub.4 ranges from about 10 to 18. In one embodiment,
the combined number of carbon atoms in R.sub.3 and R.sub.4 ranges
from about 12 to 18.
The amino acid amides can be obtained by converting the carboxylic
acid group of the amino acid to an amide group using methods well
known to those skilled in the art such as those described in J.
March, Advanced Organic Chemistry, Reaction Mechanisms and
Structure, 4.sup.th ed. John Wiley & Sons, NY, 1992, pp.
417-427. Typically, the amino acid is converted to an amino acid
derivative such as an amino acid ester or an acid chloride of the
amino acid and the amino acid derivative is then reacted with an
amine of formula NHR.sub.3R.sub.4 to provide the amino acid amide.
The amino acids and amines of formula NHR.sub.3R.sub.4 are
commercially available or can be prepared by methods well known to
those skilled in the art. When forming the derivative of the amino
acid or reacting the amino acid derivative with an amine of formula
NHR.sub.3R.sub.4, it may be necessary to protect some other
functional group of the amino acid derivative or the amine with a
protecting group that is subsequently removed after the amidation
reaction. One of ordinary skill in the art would readily know what
functional groups would need to be protected before reacting the
derivative of the amino acid with the amine of formula NHR.sub.3.
Suitable protecting groups are known to those skilled in the art
such as those described in T. W. Greene, et al Protective Groups in
Organic Synthesis, 3.sup.rd ed. (1999).
8.4 The Carboxylic Acid
The carboxylic acid can be any pharmaceutically acceptable
carboxylic acid. Typically, the carboxylic acid is a
C.sub.1-C.sub.22 carboxylic acid. Suitable carboxylic acids
include, but are not limited to, acetic acid, propanic acid,
butanoic acid, pentanoic acid, decanoic acid, hexanoic acid,
benzoic acid, caproic acid, lauric acid, myristic acid, palmitic
acid, stearic acid, palmic acid, oleic acid, linoleic acid, and
linolenic acid.
In one embodiment, the carboxylic acid is a C.sub.6-C.sub.22
carboxylic acid.
In one embodiment, the carboxylic acid is a C.sub.8-C.sub.22
carboxylic acid.
In one embodiment, the carboxylic acid is a C.sub.10-C.sub.22
carboxylic acid.
In one embodiment, the carboxylic acid is a C.sub.6-C.sub.18
carboxylic acid.
In one embodiment, the carboxylic acid is a C.sub.8-C.sub.18
carboxylic acid.
In one embodiment, the carboxylic acid is a C.sub.10-C.sub.18
carboxylic acid.
In one embodiment, the carboxylic acid is a saturated or
unsaturated fatty acid.
In one embodiment, the carboxylic acid is a saturated fatty
acid.
In one embodiment, the carboxylic acid is an unsaturated fatty
acid.
In one embodiment, the carboxylic acid is a dicarboxylic acid.
Suitable dicarboxylic acids include, but are not limited to, oxalic
acid, malonic aid, succinic acid, glutamic acid, adipic acid, and
pimelic acid.
The carboxylic acids are commercially available or can be prepared
by methods well known to those skilled in the art.
In one embodiment, the carboxylic acid is an N-acyl amino acid. The
N-acyl amino acids have the following general formula (II):
##STR00004## wherein R is the amino acid side chain and is defined
above; and R.sub.2 is an acyl group of formula --C(O)--R.sub.5,
wherein R.sub.5 is a substituted C.sub.1 to C.sub.21 hydrocarbon
group, i.e., the acyl group, R.sub.2, is a C.sub.1- to C.sub.22
acyl group. Representative acyl groups of formula --C(O)--R.sub.5
include, but are not limited to, acetyl, propionyl, butanoyl,
hexanoyl, caproyl, heptoyl, octoyl, nonoyl, decoyl, undecoyl,
dodecoyl, tridecoyl, tetradecoyl, pentadecoyl, hexadecoyl,
heptadecoyl, octadecoyl, laurolyl, myristoyl, palmitoyl, stearoyl,
palmioleoyl, oleoyl, linoleoyl, linolenoyl, and benzoyl.
In one embodiment, R.sub.5 is a C.sub.5-C.sub.21 hydrocarbon group,
i.e., the acyl group of formula --C(O)--R.sub.5 is a
C.sub.6-C.sub.22 acyl group.
In one embodiment, R.sub.5 is a C.sub.7-C.sub.21 hydrocarbon group,
i.e., the acyl group of formula --C(O)--R.sub.5 is a
C.sub.8-C.sub.22 acyl group.
In one embodiment, R.sub.5 is a C.sub.9-C.sub.21 hydrocarbon group,
i.e., the acyl group of formula --C(O)--R.sub.5 is a
C.sub.10-C.sub.22 acyl group.
In one embodiment, R.sub.5 is a C.sub.5-C.sub.17 hydrocarbon group,
i.e., the acyl group of formula --C(O)--R.sub.5 is a
C.sub.6-C.sub.18 acyl group.
In one embodiment, R.sub.5 is a C.sub.7-C.sub.17 hydrocarbon group,
i.e., the acyl group of formula --C(O)--R.sub.5 is a
C.sub.8-C.sub.18 acyl group.
In one embodiment, R.sub.5 is a C.sub.9-C.sub.17 hydrocarbon group,
i.e., the acyl group of formula --C(O)--R.sub.5 is a
C.sub.10-C.sub.18 acyl group.
In one embodiment, the acyl group of formula --C(O)--R.sub.5 is
obtained from a saturated or unsaturated fatty acid.
In one embodiment, the acyl group of formula --C(O)--R.sub.5 is a
caproyl, laurolyl, myristoyl, palmitoyl, stearoyl, palmioleoyl,
oleoyl, linoleoyl, or linolenoyl group.
The N-acylated amino acids can be obtained by methods well known to
those skilled in the art. For example, the N-acylated amino acids
can be obtained by reacting an amino acid with an acid halide of
formula T-C(O)--R.sub.5, wherein T is a halide, preferably
chloride, and R.sub.1 is as defined above, using methods well known
to those skilled in the art. When N-acylating the amino acid with
the acid halide of formula T-C(O)--R.sub.5, it may be necessary to
protect some other functional group of the amino acid or the acid
halide with a protecting group that is subsequently removed after
the acylation reaction. One of ordinary skill in the art would
readily know what functional groups would need to be protected
before acylating the amino acid with the acid halide of formula
T-C(O)--R.sub.5. Suitable protecting groups are known to those
skilled in the art such as those described in T. W. Greene, et al.
Protective Groups in Organic Synthesis, 3.sup.rd ed. (1999).
Acid halides can be obtained using methods well known to those
skilled in the art such as those described in J. March, Advanced
Organic Chemistry, Reaction Mechanisms and Structure, 4.sup.th ed.
John Wiley & Sons, NY, 1992, pp. 437-8. For example, acid
halides can be prepared by reacting a carboxylic acid with thionyl
chloride, bromide, or iodide. Acid chlorides and bromides can also
be prepared by reacting a carboxylic acid with phosphorous
trichloride or phosphorous tribromide, respectively. Acid chlorides
can also be prepared by reacting a carboxylic acid with Ph.sub.3P
in carbon tetrachloride. Acid fluorides can be prepared by reacting
a carboxylic acid with cyanuric fluoride.
8.5 The Pharmaceutically Acceptable Organic Solvent
Any pharmaceutically acceptable organic solvent can be used in the
pharmaceutical compositions of the invention. Representative,
pharmaceutically acceptable organic solvents include, but are not
limited to, pyrrolidone, N-methyl-2-pyrrolidone, polyethylene
glycol, propylene glycol (i.e., 1,3-propylene glycol), glycerol
formal, isosorbid dimethyl ether, ethanol, dimethyl sulfoxide,
tetraglycol, tetrahydrofurfuryl alcohol, triacetin, propylene
carbonate, dimethyl acetamide, dimethyl formamide, dimethyl
sulfoxide, and combinations thereof.
In one embodiment, the pharmaceutically acceptable organic solvent
is a water soluble solvent. A representative pharmaceutically
acceptable water soluble organic solvents is triacetin.
In one embodiment, the pharmaceutically acceptable organic solvent
is a water miscible solvent. Representative pharmaceutically
acceptable water miscible organic solvents include, but are not
limited to, glycerol formal, polyethylene glycol, and propylene
glycol.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises pyrrolidone. In one embodiment, the pharmaceutically
acceptable organic solvent is pyrrolidone substantially free of
another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises N-methyl-2-pyrrolidone. In one embodiment, the
pharmaceutically acceptable organic solvent is
N-methyl-2-pyrrolidone substantially free of another organic
solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises polyethylene glycol. In one embodiment, the
pharmaceutically acceptable organic solvent is polyethylene glycol
substantially free of another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises propylene glycol. In one embodiment, the pharmaceutically
acceptable organic solvent is propylene glycol substantially free
of another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises glycerol formal. In one embodiment, the pharmaceutically
acceptable organic solvent is glycerol formal substantially free of
another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises isosorbid dimethyl ether. In one embodiment, the
pharmaceutically acceptable organic solvent is isosorbid dimethyl
ether substantially free of another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises ethanol. In one embodiment, the pharmaceutically
acceptable organic solvent is ethanol substantially free of another
organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises dimethyl sulfoxide. In one embodiment, the
pharmaceutically acceptable organic solvent is dimethyl sulfoxide
substantially free of another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises tetraglycol. In one embodiment, the pharmaceutically
acceptable organic solvent is tetraglycol substantially free of
another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises tetrahydrofurfuryl alcohol. In one embodiment, the
pharmaceutically acceptable organic solvent is tetrahydrofurfuryl
alcohol substantially free of another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises triacetin. In one embodiment, the pharmaceutically
acceptable organic solvent is triacetin substantially free of
another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises propylene carbonate. In one embodiment, the
pharmaceutically acceptable organic solvent is propylene carbonate
substantially free of another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises dimethyl acetamide. In one embodiment, the
pharmaceutically acceptable organic solvent is dimethyl acetamide
substantially free of another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
comprises dimethyl formamide. In one embodiment, the
pharmaceutically acceptable organic solvent is dimethyl formamide
substantially free of another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
is propylene glycol in glycerol formal substantially free of
another organic solvent.
In one embodiment, the pharmaceutically acceptable organic solvent
is about 10 percent propylene glycol in glycerol formal.
In one embodiment, the pharmaceutically acceptable organic solvent
is a solvent that is recognized as GRAS by the FDA for
administration or consumption by animals.
In one embodiment, the pharmaceutically acceptable organic solvent
is a solvent that is recognized as GRAS by the FDA for
administration or consumption by humans.
In one embodiment, the pharmaceutically acceptable organic solvent
is substantially free of water. Pharmaceutically acceptable organic
solvents that are substantially free of water are advantageous
since they are not conducive to bacterial growth. Accordingly, it
is typically not necessary to include a preservative in
pharmaceutical compositions that are substantially free of
water.
8.6 The Pharmaceutically Active Compound
Examples of pharmaceutically active agents useful in the
composition and methods of the invention include, but are not
limited to, .alpha.-adrenergic agonists, .beta.-adrenergic
agonists, .alpha.-adrenergic blockers, .beta.-adrenergic blockers,
aldose reductase inhibitors, anabolics, analgesics (narcotic and
non-narcotic), androgens, anesthetics, anorexics, anthelmintics
(e.g., cestode, nematode, onchocerca, schistosoma, and the like),
anti-allergics, anti-ameboics, anti-androgens, anti-anginals,
anti-arrhythmics, anti-arteriosclerotics, anti-arthritics,
antibiotics and other antibacterials, anti-cholinergics,
anti-convulsants, anti-depressants, anti-diabetics agents,
anti-diarrheals, anti-diuretics, anti-estrogens, antifungals,
anti-glaucomas, anti-gonadotropins, anti-gout agents,
anti-histaminics, anti-hyperlipoproteinemics, anti-hypertensives,
anti-hyperthyroid agents, anti-hypertrophy agents,
anti-hypotensives, anti-hypothyroid agents, anti-inflammatories,
anti-malarials, antimicrobials, anti-migraine agents, anti-nausea
agents, anti-neoplastics, antioxidants, antiparasitic agents,
anti-parkinsonian agents, anti-pheochromocytoma agents,
anti-pneumocytis agents, antiproliferative agents, anti-protozoals
(e.g., leishmania, trichomonas, trypansoma, and the like),
anti-pruritic agents, anti-psoratic agents, anti-psychotic agents,
anti-pyretics, anti-rheumatics, anti ricketts agents,
anti-seborrheic agents, antiseptics, anti-spasmodic agents,
anti-thrombotic agents, antitussives, anti-ulcer agents,
anti-urolithic agents, anti-venins, antivirals, anxiolytics,
benzodiazepine antagonists, bronchodilators, calcium channel
blockers, calcium regulators, cardiotonics, chelating agents,
chemotherapeutics, cholecystokinin antagonists, cholelitholytic
agents, choleretics, cholinergics, cholinesterase inhibitors,
cholinesterase reactivators, central nervous system stimulants and
agents, decongestants, diuretics, dopamine receptor agonists, drugs
for treating or preventing pain, ectoparasiticides, enzymes, enzyme
inducers, estrogens, gastric secretion inhibitors, glucocorticoids,
gonad-stimulating principles, gonadotropic hormones, growth
hormones, growth hormone releasing factors, growth stimulants,
hemolytics, heparin agonists, hepatoprotectants, hypnotics, immune
system boosters, immunomodulators, immunosuppressants, lactation
stimulating hormones, LH-RH stimulating agonists, lipotropics,
lupus erythmatosus suppressants, mineral corticoids, miotics,
monoamine oxidase inhibitors, mucolytics, muscle relaxants,
narcotic antagonists, neuroprotectives, neotropics, ovarian
hormones, oxytocics, pepsin inhibitors, peristaltic stimulators,
progestrogens, prolactin inhibitors, protoglandins, prostoglandin
analogs, protease inhibitors, respiratory stimulants, sclerosing
agents, sedatives, steroids, thrombolytics, thyrotropic hormones,
transdermal penetration enhancers, uricosurics, vasoconstrictors,
vasodilators (e.g., cerebral, coronary, peropheral, and the like),
vasoprotectants, vitamins, vitamin source extracts, vulneraries
(including, but not limited to, those listed in U.S. Pat. No.
5,719,197, the entire disclosure of which is incorporated herein by
reference), and combinations thereof. Other additionally or
alternately acceptable pharmaceutically active agents can be found,
e.g., in U.S. Pat. No. 6,221,383, the entire disclosure of which is
incorporated herein by reference.
In one embodiment, the pharmaceutically active compound is an
antibacterial agent. Examples of useful antibacterial agents
include, but are not limited to, .beta.-lactam antibiotics such as
penicillins, amoxicillin, ampicillin, and cephalosporins; macrolide
antibiotics such as oleandomycin and erythromycin; tetracyclines
such as tetracycline, oxytetracycline, and chlortetracycline;
procaine penicillin G; quinolones such as nalidixic acid and
norfloxacin; sulfonamides; chloramphenicol; florfenicol;
thiamphenicol, aminoglycosides such as streptomycin, kanamycin, and
gentamycins; nucleoside antibiotics such as polyoxin B;
actinorhodine; bacitracin; candicidin A; ceftiofor; clindamycin;
cycloheximide; cycloserine; fosfomycin; griseofulvin;
metronidazole; monensin; novobiocin; rifampin; streptothricin;
tetranactin; tilmicosin; tylosin; actinomycin D; adriamycin;
bleomycin B2; glycolipids such as moenomycin A; mitomycin C;
nojirimycin; valinomycin; and vancomycin; (See, e.g., Bradford P.
Smith, Large Animal Internal Medicine, 2nd edn., Mosby, St. Louis,
1996, p. 644, and S. Birchard and R. Sherding, Saunders Manual of
Small Animal Practice, W.B. Saunders Company, Philadelphia, 1994,
p. 739).
In one embodiment, the pharmaceutically active compound is an
antifungal agent. Examples of useful antifungal agents include, but
are not limited to terbinafine, amphotericin B, ketaconazole,
miconazole, 5-fluorocytosine, enilconazole, itraconazole,
thiabendazole, and iodides (See, e.g., Bradford P. Smith, Large
Animal Internal Medicine, 2nd edn., Mosby, St. Louis, 1996, p. 576,
and S. Birchard and R. Sherding, Saunders Manual of Small Animal
Practice, W.B. Saunders Company, Philadelphia, 1994, p. 576).
In one embodiment, the pharmaceutically active compound is an
antiviral agent. Examples of useful antiviral agents include, but
are not limited to, interferon and adefovir (See, e.g., Bradford P.
Smith, Large Animal Internal Medicine, 2nd edn., Mosby, St. Louis,
1996, p. 646).
In one embodiment, the pharmaceutically active compound is an
antiparasitic agent. Examples of useful antiparasitic agents
include, but are not limited to, benzimidazoles, such as
thiabendazole, fenbendazole, mebendazole, oxfendazole,
oxibendazole, albendazole, parbendazole, and febantel;
tetrahydropyridines such as morantel tartrate/pyrantel pamoate;
levamisole, organophosphates such as haloxon, coumaphos,
trichlorfon, and dichlorvos; piperazine salts; ivermectin; and
phenothiazine (See, e.g., Bradford P. Smith, Large Animal Internal
Medicine, 2nd edn., Mosby, St. Louis, 1996, p. 1688).
In one embodiment, the pharmaceutically active compound is an
anti-inflammatory agent. Examples of useful antiinflammatory agents
include, but are not limited to, steroids such as betamethazone;
corticosteroids such as dexamethasone; antihistamines; and
non-steroidal antiinflammatory drugs such as aspirin, flunixin
meglumine, phenylbutazone, diclofenac, naproxen, ketoprofen,
carprofen, and ibuprofin (See, e.g., Bradford P. Smith, Large
Animal Internal Medicine, 2nd edn., Mosby, St. Louis, 1996, p.
645).
In one embodiment, the pharmaceutically active compound is a
protein.
In one embodiment, the pharmaceutically active compound is a
hormone.
In one embodiment, the pharmaceutically active compound is a
peptide.
In one embodiment, the pharmaceutically active compound is
insulin.
In one embodiment, the pharmaceutically active compound is an
anti-depressant.
In one embodiment, the pharmaceutically active compound is
fluoxetine.
One of ordinary skill in the art will readily recognize what
pharmaceutically active compounds are neutral pharmaceutically
active compounds and what pharmaceutically active compounds can
form salts.
8.7 The Pharmaceutical Compositions
8.7.1 Pharmaceutical Compositions Comprising (i) an Amino Acid
Ester or Amino Acid Amide and (ii) an Acidic Pharmaceutically
Active Compound
The amino acid ester can be any amino acid ester described
above.
The amino acid amide can be any amino acid amide described
above.
The acidic pharmaceutically active compound can be any acidic
pharmaceutically active compound.
In one embodiment, the acidic pharmaceutically active compound is
an antiinflammatory selected from aspirin, flunixin, diclofenac,
naproxen, ketoprofen, carprofen, and ibuprofen.
In one embodiment, the pharmaceutically active compound is a
phosphorylated nucleotide such as adefovir.
In one embodiment, the pharmaceutical composition is a solid.
Without wishing to be bound by theory, it is believed that the
solid is a salt formed between the amino acid ester or amino acid
amide and the acidic pharmaceutically active compound wherein the
acidic pharmaceutically active compound protonates the
.alpha.-amino group of the amino acid ester or amino acid
amide.
In one embodiment, the pharmaceutical composition further comprises
a pharmaceutically acceptable organic solvent.
The pharmaceutically acceptable organic solvent can be any
pharmaceutically acceptable organic solvent described above.
In one embodiment, the pharmaceutical composition further
comprising a solvent is a suspension of solid particles in the
pharmaceutically acceptable organic solvent. Without wishing to be
bound by theory, it is believed that the solid particles comprise a
salt formed between the amino acid ester or amino acid amide and
the acidic pharmaceutically active compound wherein the acidic
pharmaceutically active compound protonates the .alpha.-amino group
of the amino acid ester or amino acid amide.
In one embodiment, comprising a pharmaceutically acceptable organic
solvent the pharmaceutical composition is injectable and forms a
precipitate when injected into water.
When the injectable pharmaceutical compositions are injected into
water they form a precipitate. Without wishing to be bound by
theory, it is believed that the .alpha.-amino group of the amino
acid ester or amino acid amide is protonated by the acidic
pharmaceutically active compound to form a salt that is soluble in
the pharmaceutically acceptable organic solvent but insoluble in
water. Accordingly, when the pharmaceutical compositions are
injected into an animal, at least a portion of the pharmaceutical
composition precipitates at the injection site to provide a drug
depot. Without wishing to be bound by theory, it is believed that
when the pharmaceutically compositions are injected into an animal,
the pharmaceutically acceptable organic solvent diffuses away from
the injection site and aqueous bodily fluids diffuse towards the
injection site, resulting in an increase in concentration of water
at the injection site, that causes at least a portion of the
composition to precipitate and form a drug depot. The precipitate
can take the form of a solid, a crystal, a gummy mass, or a gel.
The precipitate, however, provides a depot of the pharmaceutically
active compound at the injection site that releases the
pharmaceutically active compound over time. Pharmaceutical
compositions that are suspensions can also form drug depots when
injected into an animal.
The molar ratio of acidic groups on the acidic pharmaceutically
active compound to the amino acid ester or amino acid amide is
typically about 1.5:1, preferably about 1.25:1, more preferably
about 1.1:1. and most preferably about 1:1. Accordingly, when the
acidic pharmaceutically active compound is a mono-protic carboxylic
acid the molar ratio of the acidic pharmaceutically active compound
to the amino acid ester or amino acid amide is about 1.5:1,
preferably about 1.25:1, more preferably about 1.1:1, and most
preferably about 1:1. When the acidic pharmaceutically active
compound is a dicarboxylic acid, however, the ratio of the acidic
pharmaceutically active compound to the amino acid ester or amino
acid amide is typically about 0.75:1, preferably about 0.625:1,
more preferably about 0.55:1, and most preferably about 0.5:1.
When the molar ratio of acidic groups on the acidic
pharmaceutically active compound to the amino acid ester or amino
acid amide is greater than 1, the pharmaceutical composition will
also include the non-salt or free form of the acidic
pharmaceutically active compound. Compositions further comprising
the free form of the acidic pharmaceutically active compound
provide an initial dose or "burst" of the acidic pharmaceutically
active compound when administered to an animal. Accordingly, in
some embodiments, the molar ratio of acidic groups on the acidic
pharmaceutically active compound to the amino acid ester or amino
acid amide is greater than 1 to provide a burst.
Typically, however, the pharmaceutical composition includes about 1
equivalent of amino acid ester or amino acid amide for each
equivalent of acidic functional groups in the acidic
pharmaceutically active compound so that there is substantially no
free acidic pharmaceutically active compound. For example, if the
acidic pharmaceutically active compound has a single acidic
functional group, the acidic pharmaceutical composition includes
about 1 equivalent of amino acid ester or amino acid amide for each
equivalent of acidic pharmaceutically active compound. If the
acidic pharmaceutically active compound, however, has two acidic
functional group, the acidic pharmaceutical composition typically
includes about 2 equivalent of amino acid ester or amino acid amide
for each equivalent of acidic pharmaceutically active compound.
By varying the lipophilicity and/or molecular weight of the amino
acid ester or amino acid amide it is possible to vary the rate at
which the acidic pharmaceutically active compound is released from
the drug depot. Generally, the more lipophilic the amino acid ester
or amino acid amide, the more slowly drug is released. The
lipophilicity and/or molecular weight of the amino acid ester or
amino acid amide can be varied by varying the amino acid and/or the
alcohol (or amine) used to form the amino acid ester (or amino acid
amide). For example, the lipophilicity and/or molecular weight of
the amino acid ester can be varied by varying the R.sub.1
hydrocarbon group of the amino acid ester. Typically, increasing
the length of R.sub.1 increase the lipophilicity of the amino acid
ester. Similarly, the lipophilicity and/or molecular weight of the
amino acid amide can be varied by varying the R.sub.3 or R.sub.4
group of the amino acid amide.
The combined amount of the acidic pharmaceutically active compound
and amino acid ester or amino acid amide typically ranges from
about 1 to 90 percent by weight of the pharmaceutical composition,
preferably about 5 to 80 percent by weight of the pharmaceutical
composition, more preferably about 7.5 to 70 percent by weight of
the pharmaceutical composition, and most preferably about 10 to 60
by weight of the pharmaceutical composition.
In one embodiment, the pharmaceutically active compound is
flunixin.
In one embodiment, the pharmaceutically active compound is flunixin
and the amino acid ester is tryptophan octanoate.
In one embodiment, the pharmaceutically active compound is
flunixin, the amino acid ester is tryptophan octanoate, and the
pharmaceutically acceptable organic solvent is about 5% propylene
glycol in glycerol formal.
In one embodiment, the pharmaceutically active compound is
flunixin, the amino acid ester is tryptophan octanoate, the
pharmaceutically acceptable organic solvent is about 5% propylene
glycol in glycerol formal, and the combined amount of flunixin and
the tryptophan octanoate ranges from about 25 to 40 percent by
weight of the composition.
In one embodiment, the pharmaceutically active compound is
flunixin, the amino acid ester is tryptophan octanoate, the
pharmaceutically acceptable organic solvent is about 5% propylene
glycol in glycerol formal, and the combined amount of flunixin and
the tryptophan octanoate ranges from about 30 to 35 percent by
weight of the composition.
In one embodiment, the pharmaceutically active compound is flunixin
and the amino acid ester is tryptophan butanoate.
In one embodiment, the pharmaceutically active compound is
flunixin, the amino acid ester is tryptophan butanoate, and the
pharmaceutically acceptable organic solvent is about 5% propylene
glycol in glycerol formal.
In one embodiment, the pharmaceutically active compound is
flunixin, the amino acid ester is tryptophan butanoate, the
pharmaceutically acceptable organic solvent is about 5% propylene
glycol in glycerol formal, and the combined amount of flunixin and
the tryptophan butanoate ranges from about 20 to 35 percent by
weight of the composition.
In one embodiment, the pharmaceutically active compound is
flunixin, the amino acid ester is tryptophan butanoate, the
pharmaceutically acceptable organic solvent is about 5% propylene
glycol in glycerol formal, and the combined amount of flunixin and
the tryptophan butanoate ranges from about 25 to 32 percent by
weight of the composition.
In one embodiment, the amino acid ester or amide is an amino acid
ester or amide of lysine. Without wishing to be bound by theory it
is believed that the amino acid ester or amide of lysine
cross-links two molecules of acidic pharmaceutically active
compound as depicted below for an ester of lysine:
##STR00005## wherein R.sub.1 has the meaning described above and
Drug-C(O)O.sup.- is the acidic pharmaceutically active
compound.
In one embodiment, the acidic pharmaceutically active compound is a
phosphorylated nucleotide such as adefovir.
The molar ratio of acidic groups on the pharmaceutically active
compound to amine groups on the amino acid ester or amide of lysine
typically ranges from about 1.5:1 to 1:1.5. In one embodiment, the
molar ratio of acidic groups on the pharmaceutically active
compound to amine groups on the amino acid ester or amide of lysine
ranges from about 1.25:1 to 1:1.25. In one embodiment, the molar
ratio of acidic groups on the pharmaceutically active compound to
amine groups on the amino acid ester or amide of lysine ranges from
about 1.1:1 to 1:1.1. In one embodiment, the molar ratio of acidic
groups on the pharmaceutically active compound to amine groups on
the amino acid ester or amide of lysine is about 1:1.
In one embodiment, the molar ratio of amine groups on the amino
acid ester or amide of lysine relative to acidic groups on the
pharmaceutically active compound is greater than about 1:1. In one
embodiment, the molar ratio of amine groups on the amino acid ester
or amide of lysine relative to acidic groups on the
pharmaceutically active compound is greater than about 2:1. In one
embodiment, the molar ratio of amine groups on the amino acid ester
or amide of lysine relative to acidic groups on the
pharmaceutically active compound is greater than about 5:1. In one
embodiment, the molar ratio of amine groups on the amino acid ester
or amide of lysine relative to acidic groups on the
pharmaceutically active compound is greater than about 8:1. In one
embodiment, the molar ratio of amine groups on the amino acid ester
or amide of lysine relative to acidic groups on the
pharmaceutically active compound is greater than about 10:1. In one
embodiment, the molar ratio of amine groups on the amino acid ester
or amide of lysine relative to acidic groups on the
pharmaceutically active compound is greater than about 12:1. In one
embodiment, the molar ratio of amine groups on the amino acid ester
or amide of lysine relative to acidic groups on the
pharmaceutically active compound ranges from about 2:1 to 5:1. In
one embodiment, the molar ratio of amine groups on the amino acid
ester or amide of lysine relative to acidic groups on the
pharmaceutically active compound ranges from about 2:1 to 8:1. In
one embodiment, the molar ratio of amine groups on the amino acid
ester or amide of lysine relative to acidic groups on the
pharmaceutically active compound ranges from about 2:1 to 10:1. In
one embodiment, the molar ratio of amine groups on the amino acid
ester or amide of lysine relative to acidic groups on the
pharmaceutically active compound ranges from about 2:1 to 12:1.
In one embodiment, the molar ratio of amine groups on the amino
acid ester or amide of lysine relative to acidic groups on the
pharmaceutically active compound is greater than about 1:1 and some
or all of the excess amino groups on the amino acid ester or amide
of lysine are neutralized with a fatty acid. Any of the fatty acids
described above can be used to neutralize the excess amino groups
on the amino acid ester or amide of lysine.
8.7.2 Pharmaceutical Compositions Comprising (i) an Amino Acid
Ester or Amino Acid Amide, (ii) a Carboxylic Acid, (iii) a
Pharmaceutically Active Compound or a Pharmaceutically Acceptable
Salt Thereof
The amino acid ester can be any amino acid ester described
above.
The amino acid amide can be any amino acid amide described
above.
The carboxylic acid can be any carboxylic acid described above.
In one embodiment, the carboxylic acid is a fatty acid.
In one embodiment, the carboxylic acid is an N-acylated amino
acid.
In one embodiment, the pharmaceutical composition is a solid.
Without wishing to be bound by theory, it is believed that the
solid comprises a salt formed between the amino acid ester or amino
acid amide and the carboxylic acid wherein the carboxylic acidic
protonates the .alpha.-amino group of the amino acid ester or amino
acid amide.
In one embodiment, the pharmaceutical composition further comprises
a pharmaceutically acceptable organic solvent.
The pharmaceutically acceptable organic solvent can be any
pharmaceutically acceptable organic solvent described above.
In one embodiment, the pharmaceutical composition further
comprising a pharmaceutically acceptable organic solvent is a
suspension of solid particles in the pharmaceutically acceptable
organic solvent. Without wishing to be bound by theory, it is
believed that the solid particles are a salt formed between the
amino acid ester or amino acid amide and the carboxylic acid
wherein the carboxylic acid protonates the .alpha.-amino group of
the amino acid ester or amino acid amide.
In one embodiment, comprising a pharmaceutically acceptable organic
solvent, the pharmaceutical composition is injectable and forms a
precipitate when injected into water.
The pharmaceutically active compound can be a neutral
pharmaceutically active compound or a pharmaceutically acceptable
salt of a basic or acidic pharmaceutically active compound.
In one embodiment, the pharmaceutically active compound is a
neutral pharmaceutically active compound. When the pharmaceutically
active compound is a neutral pharmaceutically active compound, the
pharmaceutical composition includes about 1 equivalent of amino
acid ester or amino acid amide for each equivalent of acidic groups
in the carboxylic acid. For example, if the carboxylic acid is a
mono-protic carboxylic acid, the pharmaceutical composition
includes about 1 equivalent of amino acid ester or amino acid amide
for each equivalent of carboxylic acid and if the carboxylic acid
is a di-carboxylic acid, the pharmaceutical composition includes
about 2 equivalent of amino acid ester or amino acid amide for each
equivalent of carboxylic acid.
In one embodiment, the pharmaceutically active compound is a
neutral pharmaceutically active compound and the carboxylic acid is
a fatty acid.
In one embodiment, the pharmaceutically active compound is a
neutral pharmaceutically active compound and the carboxylic acid is
an N-acylated amino acid.
The amount of neutral pharmaceutically active compound in the
pharmaceutical composition typically ranges from about 1 to 90
percent by weight of the pharmaceutical composition, preferably
about 5 to 80 percent by weight of the pharmaceutical composition,
more preferably about 7.5 to 70 percent by weight of the
pharmaceutical composition, and most preferably about 10 to 60 by
weight of the pharmaceutical composition.
One of ordinary skill in the art will recognize, however, that the
amount of neutral pharmaceutically active compound in the
pharmaceutical composition can vary widely depending on the neutral
pharmaceutically active compound, the solvent, the amino acid ester
or amino acid amide, and the carboxylic acid used in the
pharmaceutical composition.
The combined amount of the amino acid ester or amino acid amide and
the carboxylic acid in the pharmaceutical compositions that further
comprise a pharmaceutically acceptable organic solvent typically
ranges from about 2 percent to 50 percent by weight of the
pharmaceutical composition, preferably about 3 percent to 35
percent by weight of the pharmaceutical composition, more
preferably about 4 percent to 25 percent by weight of the
pharmaceutical composition, even more preferably about 5 percent to
20 percent by weight of the pharmaceutical composition, and most
preferably about 5 percent to 15 percent by weight of the
pharmaceutical composition.
In one embodiment, the pharmaceutically active compound is insulin,
the carboxylic acid is decanoic acid, the amino acid ester is
tyrosine decanoate, the solvent is glycerol formal, the molar ratio
of decanoic acid to tyrosine decanoate is about 1:1, the insulin is
present in an amount ranging from about 0.5 to 15 percent by weight
of the pharmaceutical composition, and the combined amount of
decanoic acid and tyrosine decanoate ranges from about 15 to 25
percent by weight of the pharmaceutical composition.
In one embodiment, the pharmaceutically active compound is
fluoxetine, the carboxylic acid is lauric acid, the amino acid
ester tyrosine butanoate, the solvent is 10 percent propylene
glycol in glycerol formal, the amount of fluoxetine ranges from
about 5 to 30 percent by weight of the composition, and the molar
ratio of fluoxetine:lauric acid:tryptophan butanoate is about
1:2:1. Pharmaceutical compositions of the invention containing
fluoxetine can be administered to dogs to treat separation anxiety
and to cats to treat spraying.
In one embodiment, the pharmaceutically active compound is a
pharmaceutically acceptable salt of an acidic or basic
pharmaceutically active compound.
In one embodiment, the salt of the pharmaceutically active compound
is a salt formed between a basic pharmaceutically active compound
and an acid.
In one embodiment, the salt of the pharmaceutically active compound
is a salt formed between a basic pharmaceutically active compound
and a carboxylic acid.
In one embodiment, the salt of the pharmaceutically active compound
is a salt formed between a basic pharmaceutically active compound
and a fatty acid.
In one embodiment, the salt of the pharmaceutically active compound
is a salt formed between a basic pharmaceutically active compound
and an N-acylated amino acid.
In one embodiment, the salt of the pharmaceutically active compound
is a salt formed between an acidic pharmaceutically active compound
and a base.
In one embodiment, the salt of the pharmaceutically active compound
is a salt formed between an acidic pharmaceutically active compound
and an amino acid ester or amino acid amide.
In one embodiment, the carboxylic acid is a fatty acid and the
pharmaceutically active compound is a pharmaceutically acceptable
salt of an acidic or basic pharmaceutically active compound.
In one embodiment, the carboxylic acid is a fatty acid and the salt
of the pharmaceutically active compound is a salt formed between a
basic pharmaceutically active compound and an acid.
In one embodiment, the carboxylic acid is a fatty acid and the salt
of the pharmaceutically active compound is a salt formed between a
basic pharmaceutically active compound and a carboxylic acid.
In one embodiment, the carboxylic acid is a fatty acid and the salt
of the pharmaceutically active compound is a salt formed between a
basic pharmaceutically active compound and a fatty acid.
In one embodiment, the carboxylic acid is a fatty acid and the salt
of the pharmaceutically active compound is a salt formed between a
basic pharmaceutically active compound and an N-acylated amino
acid.
In one embodiment, the carboxylic acid is a fatty acid and the salt
of the pharmaceutically active compound is a salt formed between an
acidic pharmaceutically active compound and a base.
In one embodiment, the carboxylic acid is a fatty acid and the salt
of the pharmaceutically active compound is a salt formed between an
acidic pharmaceutically active compound and an amino acid ester or
amino acid amide.
In one embodiment, the carboxylic acid is an N-acylated amino acid
and the pharmaceutically active compound is a pharmaceutically
acceptable salt of an acidic or basic pharmaceutically active
compound.
In one embodiment, the carboxylic acid is an N-acylated amino acid
and the salt of the pharmaceutically active compound is a salt
formed between a basic pharmaceutically active compound and an
acid.
In one embodiment, the carboxylic acid is an N-acylated amino acid
and the salt of the pharmaceutically active compound is a salt
formed between a basic pharmaceutically active compound and a
carboxylic acid.
In one embodiment, the carboxylic acid is an N-acylated amino acid
and the salt of the pharmaceutically active compound is a salt
formed between a basic pharmaceutically active compound and a fatty
acid.
In one embodiment, the carboxylic acid is an N-acylated amino acid
and the salt of the pharmaceutically active compound is a salt
formed between a basic pharmaceutically active compound and an
N-acylated amino acid.
In one embodiment, the carboxylic acid is an N-acylated amino acid
and the salt of the pharmaceutically active compound is a salt
formed between an acidic pharmaceutically active compound and a
base.
In one embodiment, the carboxylic acid is an N-acylated amino acid
and the salt of the pharmaceutically active compound is a salt
formed between an acidic pharmaceutically active compound and a
amino acid ester or amino acid amide.
When the pharmaceutically active compound is a salt of a
pharmaceutically active compound, the pharmaceutical composition
includes about 1 equivalent of amino acid ester or amino acid amide
for each equivalent of acidic groups in the carboxylic acid.
The combined concentration of the amino acid ester or amino acid
amide and the carboxylic acid in the pharmaceutical compositions
typically ranges from about 2 percent to 50 percent by weight of
the pharmaceutical composition, preferably about 3 percent to 35
percent by weight of the pharmaceutical composition, more
preferably about 4 percent to 25 percent by weight of the
pharmaceutical composition, even more preferably about 5 percent to
20 percent by weight of the pharmaceutical composition, and most
preferably about 5 percent to 15 percent by weight of the
pharmaceutical composition.
The amount of the salt of the acidic or basic pharmaceutically
active compound in the pharmaceutical compositions typically ranges
from about 1 to 90 percent by weight of the pharmaceutical
composition, preferably about 5 to 80 percent by weight of the
pharmaceutical composition, more preferably about 7.5 to 70 percent
by weight of the pharmaceutical composition, and most preferably
about 10 to 60 by weight of the pharmaceutical composition.
One of ordinary skill in the art will recognize, however, that the
amount of the salt of the acidic or basic pharmaceutically active
compound in the pharmaceutical composition can vary widely
depending on the pharmaceutically active compound, the solvent, the
amino acid ester or amino acid amide, and the carboxylic acid used
in the pharmaceutical composition.
The pharmaceutically acceptable organic solvent can be any
pharmaceutically acceptable organic solvent described above.
Again, without wishing to be bound by theory, it is believed that
when the pharmaceutical compositions further comprising a
pharmaceutically acceptable organic solvent are injected into an
animal, the pharmaceutically acceptable organic solvent diffuses
away from the injection site and aqueous bodily fluids diffuse
towards the injection site, resulting in an increase in
concentration of water at the injection site, that causes at least
a portion of the composition to precipitate and form a drug depot.
Again, when the pharmaceutical composition is injected into an
animal, the salt of the amino acid ester or amino acid amide and
the carboxylic acid precipitates to form a drug depot that slowly
releases the pharmaceutically active compound. The salt of the
pharmaceutically active compound, however, may also form a
precipitate.
In a preferred embodiment, the pharmaceutical composition comprises
the amino acid ester or amino acid amide, a fatty acid, a salt of a
pharmaceutically active compound, and a pharmaceutically acceptable
organic solvent, wherein the salt of the pharmaceutically active
compound is a salt formed between an acidic pharmaceutically active
compound and an amino acid ester or amino acid amide. In this
embodiment, a salt formed between the amino acid ester or amino
acid amide and the fatty acid precipitates and a salt formed
between the acidic pharmaceutically active compound and the amino
acid ester or amino acid amide precipitates when the pharmaceutical
composition is injected into an animal to form a drug depot that
slowly releases the pharmaceutically active compound over time.
In another preferred embodiment, the pharmaceutical composition
comprises the amino acid ester or amino acid amide, a N-acylated
amino acid, a salt of a pharmaceutically active compound, and a
pharmaceutically acceptable organic solvent, wherein the salt of
the pharmaceutically active compound is a salt formed between an
acidic pharmaceutically active compound and an amino acid ester or
amino acid amide. In this embodiment, a salt formed between the
amino acid ester or amino acid amide and the N-acylated amino acid
precipitates and a salt formed between the acidic pharmaceutically
active compound and the amino acid ester or amino acid amide
precipitates when the pharmaceutical composition is injected into
an animal to form a drug depot that slowly releases the
pharmaceutically active compound over time.
When the compositions include an amino acid ester or amino acid
amide, a carboxylic acid, and a salt of a pharmaceutically active
compound, it is recognized that there will be an exchange of the
anions (and cations) that form the salt of the pharmaceutically
active compound with the anions (and cations) that form the salt
between the carboxylic acid and the amino acid ester or amino acid
amide. For example, if the salt of a pharmaceutically active
compound is a salt formed between a basic pharmaceutically active
compound and a fatty acid and the carboxylic acid is a N-acylated
amino acid, the pharmaceutical composition will include each of the
following species: a salt between the basic pharmaceutically active
compound and the fatty acid, a salt between the basic
pharmaceutically active compound and the N-acylated amino acid, a
salt between the amino acid ester or amino acid amide and the fatty
acid, and a salt between the amino acid ester or amino acid amide
and the N-acylated amino acid. Any one or all of these species can
precipitate when the pharmaceutical composition is injected into an
animal to form a drug depot that slowly releases the
pharmaceutically active compound over time.
By varying the lipophilicity and/or molecular weight of the amino
acid ester or amino acid amide it is possible to vary the rate at
which the acidic pharmaceutically active compound is released from
the drug depot. Generally, the more lipophilic the amino acid ester
or amino acid amide, the more slowly drug is released. The
lipophilicity and/or molecular weight of the amino acid ester or
amino acid amide can be varied by varying the amino acid and/or the
alcohol (or amine) used to form the amino acid ester (or amino acid
amide). For example, the lipophilicity and/or molecular weight of
the amino acid ester can be varied by varying the R.sub.1
hydrocarbon group of the amino acid ester. Typically, increasing
the length of R.sub.1 increase the lipophilicity of the amino acid
ester. Similarly, the lipophilicity and/or molecular weight of the
amino acid amide can be varied by varying the R.sub.3 or R.sub.4
group of the amino acid amide. The rate at which the
pharmaceutically active compound is released from the drug depot
can also be varied by varying the lipophilicity and/or molecular
weight of the carboxylic acid. Generally, the more lipophilic the
carboxylic acid, the more slowly drug is released. The
lipophilicity and/or molecular weight of the carboxylic acid can be
varied by varying the molecular weight of the carboxylic acid.
Generally, the higher the molecular weight of the carboxylic acid,
the more slowly drug is released. Similarly, the lipophilicity
and/or molecular weight of the N-acyl amino acid can be varied by
varying the R.sub.5 group of the N-acyl amino acid.
8.7.3 Pharmaceutical Compositions Comprising (i) an N-Acyl Amino
Acid, and (ii) a Basic Pharmaceutically Active Compound
The N-acyl amino acid can be any N-acyl amino acid described
above.
The basic pharmaceutically active compound can be any basic
pharmaceutically active compound.
In one embodiment, the basic pharmaceutically active compound is an
antibiotic selected from the group consisting of penicillin,
streptomycin, azithromycin, roxythromycin, tilmicosin,
oxytetracycline, and doxycyline.
In one embodiment, the pharmaceutical composition is a solid.
Without wishing to be bound by theory, it is believed that the
solid is a salt formed between the N-acyl amino acid and the basic
pharmaceutically active compound wherein the N-acyl amino acid
protonates the basic pharmaceutically active compound.
In one embodiment, the pharmaceutical composition further comprises
a pharmaceutically acceptable organic solvent.
The pharmaceutically acceptable organic solvent can be any
pharmaceutically acceptable organic solvent described above.
In one embodiment, the pharmaceutical composition further
comprising a solvent is a suspension of solid particles in the
pharmaceutically acceptable organic solvent. Without wishing to be
bound by theory, it is believed that the solid particles are a salt
formed between the N-acyl amino acid and the basic pharmaceutically
active compound wherein the N-acyl amino acid protonates the basic
pharmaceutically active compound.
In one embodiment, comprising a pharmaceutically acceptable organic
solvent the pharmaceutical composition is injectable and forms a
precipitate when injected into water.
When the injectable pharmaceutical compositions further comprising
a solvent are injected into water they typically form a
precipitate. Without wishing to be bound by theory, it is believed
that the carboxylic acid group of the N-acyl amino acid protonates
the basic pharmaceutically active compound to form a salt that is
soluble in the pharmaceutically acceptable organic solvent but
insoluble in water. Accordingly, when the pharmaceutical
compositions are injected into an animal, at least a portion of the
pharmaceutical composition precipitates at the injection site to
provide a drug depot. Without wishing to be bound by theory, it is
believed that when the pharmaceutically compositions are injected
into an animal, the pharmaceutically acceptable organic solvent
diffuses away from the injection site and aqueous bodily fluids
diffuse towards the injection site, resulting in an increase in
concentration of water at the injection site, that causes at least
a portion of the composition to precipitate and form a drug depot.
The precipitate can take the form of a solid, a crystal, a gummy
mass, or a gel. The precipitate, however, provides a depot of the
pharmaceutically active compound at the injection site that
releases the pharmaceutically active compound over time.
Pharmaceutical compositions that are suspensions can also form a
drug depot when injected into an animal.
The molar ratio of basic groups on the basic pharmaceutically
active compound to the N-acyl amino acid is typically about 1.5:1,
preferably about 1.25:1, more preferably about 1.1:1. and most
preferably about 1:1. Accordingly, when the basic pharmaceutically
active compound is a mono-basic compound the molar ratio of the
basic pharmaceutically active compound to the N-acyl amino acid is
about 1.5:1, preferably about 1.25:1, more preferably about 1.1:1,
and most preferably about 1:1. When the basic pharmaceutically
active compound is a dibasic compound, however, the ratio of the
basic pharmaceutically active compound to the N-acyl amino acid is
typically about 0.75:1, preferably about 0.625:1, more preferably
about 0.55:1, and most preferably about 0.5:1.
When the molar ratio of basic groups on the basic pharmaceutically
active compound to the N-acyl amino acid is greater than 1, the
pharmaceutical composition will also include the non-salt or free
form of the basic pharmaceutically active compound. Compositions
further comprising the free form of the basic pharmaceutically
active compound provide an initial dose or "burst" of the basic
pharmaceutically active compound. Accordingly, in some embodiments,
the molar ratio of basic groups on the basic pharmaceutically
active compound to the N-acyl amino acid is greater than 1 to
provide a burst.
Typically, however, the pharmaceutical composition includes about 1
equivalent of N-acyl amino acid for each equivalent of basic
functional groups in the basic pharmaceutically active compound so
that there is substantially no free basic pharmaceutically active
compound. For example, if the basic pharmaceutically active
compound has a single basic functional group, the basic
pharmaceutical composition includes about 1 equivalent of N-acyl
amino acid for each equivalent of basic pharmaceutically active
compound. If the basic pharmaceutically active compound, however,
has two basic functional group, the pharmaceutical composition
typically includes about 2 equivalent of N-acyl amino acid for each
equivalent of basic pharmaceutically active compound.
By varying the lipophilicity and/or molecular weight of the N-acyl
amino acid it is possible to vary the rate at which the basic
pharmaceutically active compound is released from the drug depot.
Generally, the more lipophilic the N-acyl amino acid, the more
slowly drug is released. The lipophilicity and/or molecular weight
of the N-acyl amino acid can be varied by varying the amino acid
and/or the acyl group used to form the N-acyl amino acid. For
example, the lipophilicity and/or molecular weight of the N-acyl
amino acid can be varied by varying the R.sub.5 hydrocarbon group
of the N-acyl amino acid. Typically, increasing the length of
R.sub.5 increase the lipophilicity of the N-acyl amino acid.
The combined amount of the basic pharmaceutically active compound
and N-acyl amino acid in the pharmaceutical composition typically
ranges from about 1 to 90 percent by weight of the pharmaceutical
composition, preferably about 5 to 80 percent by weight of the
pharmaceutical composition, more preferably about 7.5 to 70 percent
by weight of the pharmaceutical composition, and most preferably
about 10 to 60 by weight of the pharmaceutical composition.
In one embodiment, the basic pharmaceutically active compound is a
fluoroquinolone. The fluoroquinolone can be any fluoroquinolone
known to those skilled in the art. Representative fluoroquinolones
useful in the compositions and methods of the invention include,
but are not limited to, those described in BE 870,576, U.S. Pat.
No. 4,448,962, DE 3,142,854, EP 047,005, EP 206,283, BE 887,574, EP
221,463, EP 140,116, EP 131,839, EP 154,780, EP 078,362, EP
310,849, EP 520,240, U.S. Pat. No. 4,499,091, U.S. Pat. No.
4,704,459, U.S. Pat. No. 4,795,751, U.S. Pat. No. 4,668,784, and
U.S. Pat. No. 5,532,239, the contents of which are expressly
incorporated herein by reference thereto.
Representative fluoroquinolones useful in the compositions and
methods of the invention include, but are not limited to,
ciprofloxacin (commercially available as Cipro.RTM., enrofloxacin
(commercially available as Baytril.RTM.), enoxacin (commercially
available as Penetrex.RTM., gatifloxacin (commercially available as
Tequin.RTM.), gemifloxacin (commercially available as
Factive.RTM.), levofloxacin (commercially available as
Levaquin.RTM.), lomefloxacin (commercially available as
Maxaquin.RTM.), moxifloxacin (commercially available as
Avelox.RTM.), norfloxacin (commercially available as Noroxin.RTM.,
ofloxacin (commercially available as Floxin.RTM.), sparfloxacin
(commercially available as Zagam.RTM.), trovafloxacin (commercially
available as Trovan.RTM.), difloxacin, cinofloxacin, pefloxacin,
tosufloxacin, temafloxacin, flerofloxacin, amifloxacin,
benofloxacin, danofloxacin, flerofloxacin, marbofloxacin,
ruflocaxin, and sarafloxacin.
In one embodiment, the fluoroquinolone is ciprofloxacin.
In one embodiment, the fluoroquinolone is enrofloxacin.
In one embodiment, the fluoroquinolone is gatifloxacin.
In one embodiment, the fluoroquinolone is gemifloxacin.
In one embodiment, the fluoroquinolone is levofloxacin.
In one embodiment, the fluoroquinolone is lomefloxacin.
In one embodiment, the fluoroquinolone is moxifloxacin.
In one embodiment, the fluoroquinolone is ofloxacin.
In one embodiment, the fluoroquinolone is sparfloxacin.
In one embodiment, the fluoroquinolone is trovafloxacin.
In one embodiment, the fluoroquinolone is difloxacin.
In one embodiment, the fluoroquinolone is cinofloxacin.
In one embodiment, the fluoroquinolone is pefloxacin.
In one embodiment, the fluoroquinolone is tosufloxacin.
In one embodiment, the fluoroquinolone is temafloxacin.
In one embodiment, the fluoroquinolone is flerofloxacin.
In one embodiment, the fluoroquinolone is amifloxacin.
In one embodiment, the fluoroquinolone is benofloxacin.
In one embodiment, the fluoroquinolone is danofloxacin.
In one embodiment, the fluoroquinolone is flerofloxacin.
In one embodiment, the fluoroquinolone is marbofloxacin.
In one embodiment, the fluoroquinolone is ruflocaxin.
In one embodiment, the fluoroquinolone is sarafloxacin.
8.7.4 General Characteristics of the Pharmaceutical
Compositions
Typically, when the compositions of the invention are injected into
water the resulting precipitate is a gummy mass or a gel.
Typically, the viscosity of the gummy mass or a gel ranges from
about 10,000 cP to 150,000 cP. In one embodiment, the viscosity of
the gummy mass or a gel ranges from about 50,000 cP to 150,000 cP.
In one embodiment, the viscosity of the gummy mass or a gel ranges
from about 65,000 centipoise (cP) to 150,000 cP. In one embodiment,
the viscosity of the gummy mass or a gel ranges from about 75,000
centipoise (cP) to 150,000 cP. The viscosity of the gummy mass or
gel can be determined by injecting the pharmaceutical composition
into water to provide the gummy mass or gel, removing the water and
pharmaceutically acceptable organic solvent by filtering through a
0.22 .mu.m filter to collect the gummy mass or gel, and then
measuring the viscosity of the gummy mass or gel. Viscosity can be
measured, for example, using a Brookfield DV-E Viscometer
(commercially available from Brookfield of Middleboro, Mass.). In
another embodiment, the precipitate is a solid, i.e., resistant to
flow. In another embodiment, the solid is a crystalline solid.
The rate of release of the pharmaceutically active compound from
the drug depot can be controlled by varying the lipophilicity
and/or molecular weight of the amino acid ester or amino acid
amide. Typically, if the amino acid ester is more lipophilic the
drug is released more slowly. The lipophilicity and/or molecular
weight of the amino acid ester can be varied by varying the R.sub.1
hydrocarbon group of the amino acid ester. Typically, increasing
the length of R.sub.1 increase the lipophilicity of the amino acid
ester. Similarly, the lipophilicity and/or molecular weight of the
amino acid amide can be varied by varying the R.sub.3 or R.sub.4
group of the amino acid amide.
The carboxylic acid used in the pharmaceutical composition also
affects the rate of release of the pharmaceutically active compound
from the drug depot. Similarly, when the carboxylic acid is an
N-acyl amino acid, the rate of release of the pharmaceutically
active compound from the drug depot can be controlled by varying
the lipophilicity and/or molecular weight of the N-acyl amino acid.
Again, if the carboxylic acid or N-acyl amino acid is more
lipophilic the drug is released more slowly. The lipophilicity
and/or molecular weight of the carboxylic acid can be varied by
varying the number of carbon atoms in the carboxylic acid. The
lipophilicity and/or molecular weight of the N-acyl amino acid can
be varied by varying the hydrocarbon group, R.sub.5, of the acyl
group, R.sub.2, i.e., by varying the acyl group of formula
--C(O)--R.sub.5.
The pharmaceutical compositions may further include one or more
additional excipients or additives well known to those of ordinary
skill in the art. For example, the pharmaceutical formulations may
include a preservative to inhibit microbial growth. Suitable
preservatives include, but are not limited to, parabens such as
methyl, ethyl, and propyl parabens; chlorobutanol; sodium benzoate;
myristyl-gamma-picolinium chloride; benzyl alcohol; and ethyl
alcohol. Preservatives, when present, are typically present in an
amount of about 5 mg to 250 mg per mL of pharmaceutical composition
and preferably about 5 mg to 100 mg per mL of pharmaceutical
composition.
In one embodiment, the compositions include a local anesthetic such
as lidocaine to lessen pain at the site of the injection.
Solid pharmaceutical compositions may further comprise additional
excipients well known to those of ordinary skill in the art, such
as binders, diluents, lubricants. Examples off suitable excipients
are described in Remington's Pharmaceutical Sciences (Alfonso
Gennaro ed., 19th ed. 1995), incorporated herein by reference.
Accordingly, the solid pharmaceutical compositions can be
formulated as a tablet, for oral administration, using methods will
known to those skilled in the art (Remington's Pharmaceutical
Sciences (Alfonso Gennaro ed., 19th ed. 1995).
Similarly, the pharmaceutical compositions in the form of a gel can
be formulated for oral administration by encapsulating the
pharmaceutical composition in a capsule, such as a hard or soft
gelatin capsule.
The components of the pharmaceutical composition (the amino acid
ester or amino acid amide, the carboxylic acid, the organic
solvent, and the pharmaceutically active compound, as well as any
other optional components) are preferably biocompatible and
non-toxic and, over time, are simply absorbed and/or metabolized by
the body.
8.8 Manufacturing the Pharmaceutical Compositions
To prepare the pharmaceutical compositions of the invention
comprising (i) an amino acid ester or amino acid amide, (ii) an
acidic pharmaceutically active compound, and (iii) a
pharmaceutically acceptable organic solvent, the amino acid ester
or amino acid amide and the acidic pharmaceutically active compound
are simply dissolved in the pharmaceutically acceptable organic
solvent to provide a solution (typically about 90% of the amount of
the solvent desired in the final pharmaceutical composition).
Additional excipients and/or additives can then be dissolved in the
solution. Additional pharmaceutically acceptable organic solvent is
then added to provide the desired concentration of the amino acid
ester or amino acid amide and the acidic pharmaceutically active
compound in the pharmaceutical composition The solution of the
amino acid ester or amino acid amide and the acidic
pharmaceutically active compound, and additional excipients and/or
additives can then be filtered, preferably sterile filtered,
directly into bottles.
The solid pharmaceutical compositions comprising a (i) an amino
acid ester or amino acid amide and (ii) an acidic pharmaceutically
active compound are prepared in the same way as is used to prepare
the pharmaceutical compositions of the invention comprising (i) an
amino acid ester or amino acid amide, (ii) an acidic
pharmaceutically active compound, and (iii) a pharmaceutically
acceptable organic solvent, and the pharmaceutically acceptable
organic solvent is simply removed by evaporation. In one
embodiment, the pharmaceutically acceptable organic solvent is
removed under reduced pressure. Alternatively, the pharmaceutical
composition comprising (i) an amino acid ester or amino acid amide,
(ii) an acidic pharmaceutically active compound, and (iii) a
pharmaceutically acceptable organic solvent can be diluted with
water to provide a solid precipitate and the solid precipitate
collected by filtration and, optionally, dried. The resulting solid
pharmaceutical composition can optionally be milled to provide
smaller particles. Excipients can also be added to the resulting
solid pharmaceutical compositions.
Similarly, to prepare the pharmaceutical compositions of the
invention comprising (i) an amino acid ester or amino acid amide,
(ii) a carboxylic acid, (iii) a neutral pharmaceutically active
compound or a pharmaceutically acceptable salt of a
pharmaceutically active compound, and (iv) a pharmaceutically
acceptable organic solvent, the amino acid ester or amino acid
amide, the carboxylic acid, and the neutral pharmaceutically active
compound or a pharmaceutically acceptable salt of a
pharmaceutically active compound are simply dissolved in the
pharmaceutically acceptable organic solvent to provide a solution
(typically about 90% of the amount of the solvent desired in the
final pharmaceutical composition). Additional excipients and/or
additives can then be dissolved in the solution. Additional
pharmaceutically acceptable organic solvent is then added to
provide the desired concentration of the amino acid ester or amino
acid amide, the carboxylic acid, and the neutral pharmaceutically
active compound or pharmaceutically acceptable salt of a
pharmaceutically active compound in the pharmaceutical composition
The solution of the amino acid ester or amino acid amide, the
carboxylic acid, the neutral pharmaceutically active compound or
pharmaceutically acceptable salt of a pharmaceutically active
compound, and additional excipients and/or additives can then be
filtered, preferably sterile filtered, directly into bottles.
The solid pharmaceutical compositions comprising a (i) an amino
acid ester or amino acid amide, (ii) a carboxylic acid, and a (iii)
a neutral pharmaceutically active compound or a pharmaceutically
acceptable salt of a pharmaceutically active compound are prepared
in the same way as is used to prepare the pharmaceutical
compositions of the invention comprising (i) an amino acid ester or
amino acid amide, (ii) a carboxylic acid, and a (iii) a neutral
pharmaceutically active compound or a pharmaceutically acceptable
salt of a pharmaceutically active compound and (iv) a
pharmaceutically acceptable organic solvent, and the
pharmaceutically acceptable organic solvent is simply removed by
evaporation. In one embodiment, the pharmaceutically acceptable
organic solvent is removed under reduced pressure. Alternatively,
the pharmaceutical composition comprising (i) an amino acid ester
or amino acid amide, (ii) a carboxylic acid, a (iii) a neutral
pharmaceutically active compound or a pharmaceutically acceptable
salt of a pharmaceutically active compound, and a pharmaceutically
acceptable organic solvent can be diluted with water to provide a
solid precipitate and the solid precipitate collected by filtration
and, optionally, dried. The resulting solid pharmaceutical
composition can optionally be milled to provide smaller particles.
Excipients can also be added to the resulting solid pharmaceutical
compositions.
Similarly, to prepare the pharmaceutical compositions of the
invention comprising (i) a N-acyl amino acid, (ii) a basic
pharmaceutically active compound, and (iii) a pharmaceutically
acceptable organic solvent, the N-acyl amino acid and the basic
pharmaceutically active compound are simply dissolved in the
pharmaceutically acceptable organic solvent to provide a solution
(typically about 90% of the amount of the solvent desired in the
final pharmaceutical composition). Additional excipients and/or
additives can then be dissolved in the solution. Additional
pharmaceutically acceptable organic solvent is then added to
provide the desired concentration of the N-acyl amino acid and the
basic pharmaceutically active compound in the pharmaceutical
composition The solution of the N-acyl amino acid ester and the
basic pharmaceutically active compound, and additional excipients
and/or additives can then be filtered, preferably sterile filtered,
directly into bottles.
The solid pharmaceutical compositions comprising a (i) a N-acyl
amino acid and (ii) a basic pharmaceutically active compound are
prepared in the same way as is used to prepare the pharmaceutical
compositions of the invention comprising (i) a N-acyl amino acid,
(ii) a basic pharmaceutically active compound, and (iii) a
pharmaceutically acceptable organic solvent, and the
pharmaceutically acceptable organic solvent is simply removed by
evaporation. In one embodiment, the pharmaceutically acceptable
organic solvent is removed under reduced pressure. Alternatively,
the pharmaceutical composition comprising (i) a N-acyl amino acid,
(ii) a basic pharmaceutically active compound, and (iii) a
pharmaceutically acceptable organic solvent can be diluted with
water to provide a solid precipitate and the solid precipitate
collected by filtration and, optionally, dried. The resulting solid
pharmaceutical composition can optionally be milled to provide
smaller particles. Excipients can also be added to the resulting
solid pharmaceutical compositions.
The pharmaceutical compositions can be sterilized using an
autoclave.
The invention further relates to a method of manufacturing the
pharmaceutical composition of the invention.
8.9. Methods of Treating a Condition in an Animal
The invention further relates to a method of treating a condition
in an animal. The method comprises administering to an animal in
need thereof an effective amount of a pharmaceutically active
compound. The pharmaceutical compositions of the invention can be
administered by injection or orally.
Solid pharmaceutical compositions can be administered by implanting
the solid pharmaceutical composition under the skin of the animal.
Solid pharmaceutical compositions, however, may also be
administered by injecting an animal with a suspension of the solid
pharmaceutical composition in a pharmaceutically acceptable organic
solvent.
The pharmaceutical compositions of the invention in the form of a
solid, a crystal, a gummy mass or a gel can also be administered
orally. For example, encapsulating the pharmaceutical formulations
in the form of a solid, a crystal, a gummy mass or a gel in a
capsule provides a dosage form that can be administered orally.
Furthermore, solid pharmaceutical compositions of the invention can
be combined with an excipient such as a binder, diluent, or
lubricant and formulated into a tablet to provide a dosage form for
oral administration. See, for example, Remington's Pharmaceutical
Sciences, Alfonso Gennaro ed., 19th ed. 1995), incorporated herein
by reference. Oral dosage forms can be designed to release the
pharmaceutically active compound in the stomach immediately or
almost immediately or to provide sustained release of the
pharmaceutically active compound in the stomach. The rate of
release of the pharmaceutically active compound is varied by
varying the lipophilicity and/or molecular weight of the components
of the pharmaceutical composition.
Injectable pharmaceutical compositions are administered to an
animal by injecting the animal with the pharmaceutical composition.
When the injectable pharmaceutical compositions are injected into
an animal, the pharmaceutical compositions form a depot that
provides sustained-release of the pharmaceutically active compound.
Pharmaceutical compositions that are a suspension of the solid
pharmaceutical composition in a pharmaceutically acceptable organic
solvent can also form a depot that provides sustained-release of
the pharmaceutically active compound when injected into an animal.
The components of the pharmaceutical composition, i.e., the amino
acid ester or amino acid amide, the carboxylic acid, and the
pharmaceutically acceptable organic solvent are biocompatible and
non-toxic and, over time, are simply absorbed and/or metabolized by
the body. The pharmaceutical compositions of the invention, can
also be administered by other routes including, but not limited to,
topical, oral, rectal, vaginal, and nasal.
The pharmaceutical compositions of the invention can provide an
effective amount of the pharmaceutically active compound to the
animal for a period of up to 15 days, and even longer, depending on
components of the pharmaceutical composition, i.e., the
pharmaceutically active compound or pharmaceutically acceptable
salt thereof, the amino acid ester, the carboxylic acid, and the
pharmaceutically acceptable organic solvent.
In one embodiment, the pharmaceutical composition provides an
effective amount of the pharmaceutically active compound or a
pharmaceutically acceptable salt thereof for up to about 3
days.
In one embodiment, the pharmaceutical composition provides an
effective amount of the pharmaceutically active compound or a
pharmaceutically acceptable salt thereof for up to about 4
days.
In one embodiment, the pharmaceutical composition provides an
effective amount of the pharmaceutically active compound or a
pharmaceutically acceptable salt thereof for up to about 6
days.
In one embodiment, the pharmaceutical composition provides an
effective amount of the pharmaceutically active compound or a
pharmaceutically acceptable salt thereof for up to about 8
days.
In one embodiment, the pharmaceutical composition provides an
effective amount of the pharmaceutically active compound or a
pharmaceutically acceptable salt thereof for up to about 10
days.
In one embodiment, the pharmaceutical composition provides an
effective amount of the pharmaceutically active compound or a
pharmaceutically acceptable salt thereof for up to about 12
days.
In one embodiment, the pharmaceutical composition provides an
effective amount of the pharmaceutically active compound or a
pharmaceutically acceptable salt thereof for up to about 15
days.
The pharmaceutical compositions are useful in human medicine and
veterinary medicine. The pharmaceutical compositions are
particularly useful in veterinary medicine.
In one embodiment, the animal is a human.
In one embodiment, the animal is a cat.
In one embodiment, the animal is a dog.
In one embodiment, the animal is a cow.
In one embodiment, the animal is a pig.
In one embodiment, the animal is a sheep.
In one embodiment, the animal is a horse.
Typically, the pharmaceutical composition further comprising a
pharmaceutically acceptable organic solvent are injected in an
amount of between about 0.2 mL and 15 mL, preferably between about
0.5 mL and 12 mL, more preferably between about 1 mL and 10 mL. The
precise dose to be administered will depend on the seriousness of
the condition, and the animal being treated and can be decided
according to the judgment of a practitioner and/or each animal's
circumstances. Smaller animals typically receive smaller injection
volumes. For example, the injection volume for a cat is typically
about 1 mL and the injection volume for a dog is typically between
about 1 mL and 2 mL. For large animals such as cows and horses,
however, the injection volume can be as large as 10 mL and even
larger. The amount of the pharmaceutical composition administered
to an animal can be determined by standard clinical techniques. In
addition, in vitro or in vivo assays can optionally be employed to
help identify optimal dosage ranges.
The pharmaceutical composition further comprising a
pharmaceutically acceptable organic solvent can be administered,
for example, by an intramuscular, intraperitoneal, or subcutaneous
injection.
Solid pharmaceutical compositions are typically administered by
implanting the solid pharmaceutical compositions containing between
about 0.01 and 2 g, preferably between about 0.2 g and 1.5 g, of
the pharmaceutically active compound or pharmaceutically acceptable
salt thereof under the skin of the animal using methods well known
to one of ordinary skill in the art. Solid pharmaceutical
compositions can also be administered by injecting a suspension of
the solid composition in a solvent. The solid pharmaceutical
composition can be suspended in an aqueous solvent or an organic
solvent
Pharmaceutical compositions for oral administered are typically in
the form of a capsule or tablet and typically contain between about
0.001 g and 2 g, preferably between about 0.01 g and 1.5 g, the
pharmaceutically active compound or pharmaceutically acceptable
salt thereof.
The pharmaceutical compositions of the invention, can also be
administered by other routes including, but not limited to,
topical, rectal, vaginal, and nasal.
Advantageously, the pharmaceutical compositions, by providing
sustained release of the pharmaceutically active compound, have
reduced toxicity, particularly in small animal such as cats and
dogs. Accordingly, the pharmaceutical compositions of the invention
have a better therapeutic profile that conventional immediate
release formulations. The methods of the invention, which involve
administering a pharmaceutically active compound to an animal by
injecting the animal with a pharmaceutical composition of the
invention, permit pharmaceutically active compounds to be
administered to animals that could, if administered in presently
available dosage forms, result in toxicity and even death of the
animal being treated. By providing sustained release of the
pharmaceutically active compound, the pharmaceutical compositions
of the invention need to be administered less frequently and
therefore are also easier to administer, more convenient, and more
cost effective than conventional modes of administering
pharmaceutically active compounds.
8.10 Kits
The invention encompasses kits that can simplify the administration
of a pharmaceutically active compound to an animal. A typical kit
of the invention comprises a unit dosage form of a pharmaceutical
composition of the invention. In one embodiment, the unit dosage
form is a container, such as a vial, which can be sterile,
containing a pharmaceutical composition of the invention. The kit
can further comprise a label or printed instructions instructing
the use of the pharmaceutically active compound to treat a
condition. In another embodiment, the kit comprises a unit dosage
form of a pharmaceutical composition of the invention and a syringe
for administering the pharmaceutical composition.
The following examples are set forth to assist in understanding the
invention and should not be construed as specifically limiting the
invention described and claimed herein. Such variations of the
invention, including the substitution of all equivalents now known
or later developed, which would be within the purview of those
skilled in the art, and changes in formulation or minor changes in
experimental design, are to be considered to fall within the scope
of the invention incorporated herein.
9. EXAMPLES
9.1 Preparation of Amino Acid Esters
Tryptophan butanoate: 1 g of tryptophan butanoate hydrochloride
salt (commercially available from Sigma-Aldrich, St. Louis, Mo.
(www.sima-aldrich.com)) was suspended in 25 mL of dichloromethane
and 600 .mu.l of triethylamine was added to the suspension with
stirring. Stirring was continued for 15 min and the resulting
solution was transferred to a separatory funnel. The organic
solution was washed twice with 25 mL of water followed by 25 mL of
saturated aqueous sodium bicarbonate. The organic layer was then
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to provide tryptophan butanoate. The structure was
confirmed using mass spectroscopy.
Tryptophan octanoate: 4 g of tryptophan butanoate hydrochloride
salt (commercially available from Sigma-Aldrich, St. Louis, Mo.
(www.sima-aldrich.com)) was suspended in 100 mL of dichloromethane
and 3 ml of triethylamine was added to the suspension with
stirring. Stirring was continued for 15 min and the resulting
solution was transferred to a separatory funnel. The organic
solution was washed twice with 25 mL of water followed by 25 mL of
saturated aqueous sodium bicarbonate. The organic layer was then
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to provide tryptophan octanoate. The structure was
confirmed using mass spectroscopy.
Tyrosine butanoate: 18.19 g of tyrosine was suspended in a solution
of 9.8 g of concentrated sulfuric acid, 40 mL water, 40 mL of
butanol, and 200 mL of toluene in a 500 mL round bottom flask
equipped with a condenser and a Dean-Stark apparatus. The resulting
solution was heated at reflux temperature until no more water could
be distilled. The resulting solution was cooled in an ice bath,
which caused the solution to separate into two phases. The upper
phase was discarded and the lower phase, an oily syrup, was
retained. The syrup was mixed with sufficient 5% aqueous sodium
bicarbonate solution to neutralize acidic impurities to provide a
solid that was collected by filtration and washed with cold water.
The resulting solid was re-crystallized in ethyl acetate.
Isoleucine butyrate: 26.23 g of isoleucine was dissolved in a
solution of 20 g of concentrated sulfuric acid, 20 mL water, 40 mL
of butanol, and 200 mL of toluene in a 500 mL round bottom flask
equipped with a condenser and a Dean-Stark apparatus. The resulting
solution was heated at reflux temperature until no more water could
be distilled. The resulting solution was then cooled to room
temperature and washed with saturated aqueous sodium bicarbonate to
neutralize acidic impurities, washed with saturated brine, and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the resulting liquid distilled under vacuum to
provide isoleucine butyrate as a colorless liquid.
Phenylalanine butyrate: 16.52 g of isoleucine was dissolved in a
solution of 10 g of concentrated sulfuric acid, 20 mL water, 20 mL
of butanol, and 200 mL of toluene in a 500 mL round bottom flask
equipped with a condenser and a Dean-Stark apparatus. The resulting
solution was heated at reflux temperature until no more water could
be distilled. The resulting solution was then cooled to room
temperature and washed with saturated aqueous sodium bicarbonate to
neutralize acidic impurities, washed with saturated brine, and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the resulting liquid distilled under vacuum to
provide phenylalanine butyrate.
Phenylalanine octanoate: 16.52 g of phenylalanine was dissolved in
a solution of 10 g of concentrated sulfuric acid, 20 mL water, 20
mL of octanol, and 120 mL of toluene in a 500 mL round bottom flask
equipped with a condenser and a Dean-Stark apparatus. The resulting
solution was heated at reflux temperature until no more water could
be distilled. The resulting solution was then cooled to room
temperature and washed with saturated aqueous sodium bicarbonate to
neutralize acidic impurities, washed with saturated brine, and
dried over anhydrous sodium sulfate. The solvent was then removed
under reduced pressure to provide phenylalanine octanoate as a
white solid that was purified using a silica gel column eluted with
a 1:9 methanol:dichloromethane mixture.
Phenylalanine dodecanoate: 16.52 g of phenylalanine was dissolved
in a solution of 10 g of concentrated sulfuric acid, 20 mL water,
20 mL of dodecanol, and 120 mL of toluene in a 500 mL round bottom
flask equipped with a condenser and a Dean-Stark apparatus. The
resulting solution was heated at reflux temperature until no more
water could be distilled. The resulting solution was then cooled to
room temperature and washed with saturated aqueous sodium
bicarbonate to neutralize acidic impurities, washed with saturated
brine, and dried over anhydrous sodium sulfate. The solvent was
then removed under reduced pressure to provide phenylalanine
dodecanoate as a solid that was purified using a silica gel column
eluted with a 1:9 methanol:dichloromethane mixture.
Tyrosine octanoate: 9.06 g of tyrosine was dissolved in a solution
of 10 g of concentrated sulfuric acid, 20 mL water, 10 mL of
octanol, and 200 mL of toluene in a 500 mL round bottom flask
equipped with a condenser and a Dean-Stark apparatus. The resulting
solution was heated at reflux temperature until no more water could
be distilled. The resulting solution was then cooled to room
temperature and washed with saturated aqueous sodium bicarbonate to
neutralize acidic impurities to provide an emulsion. About 150 mL
of ethylacetate was added to the emulsion to provide two phases.
The aqueous phase was discarded and the organic phase washed with
saturated Brine and dried over anhydrous sodium sulfate. The
solvent was the removed under reduced pressure to provide tyrosine
octanoate as a white solid that was purified using a silica gel
column eluted with a 1:9 methanol:dichloromethane mixture.
Isoleucine octanoate: 13.1 g of isoleucine was dissolved in a
solution of 10 g of concentrated sulfuric acid, 20 mL water, 20 mL
of octanol, and 200 mL of toluene in a 500 mL round bottom flask
equipped with a condenser and a Dean-Stark apparatus placed in an
oil bath. The resulting solution was heated at reflux temperature
until no more water could be distilled. The resulting solution was
then cooled to room temperature, diluted with 120 mL of ethyl
acetate and the organic layer washed with saturated aqueous sodium
bicarbonate to neutralize acidic impurities, washed with saturated
Brine, and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the resulting liquid distilled
to provide isoleucine octanoate as a colorless liquid.
Proline butanoate: 34.5 g of proline was suspended in a solution of
35 g of concentrated sulfuric acid, 40 mL water, 120 mL of butanol,
and 200 mL of toluene in a 500 mL round bottom flask equipped with
a condenser and a Dean-Stark apparatus. The resulting solution was
heated at reflux temperature until no more water could be
distilled. The resulting solution was then cooled to room
temperature, washed with saturated aqueous sodium bicarbonate to
neutralize acidic impurities, washed with saturated Brine, and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the resulting liquid distilled to provide
proline butanoate as a colorless liquid.
9.2 Pharmaceutical Compositions Containing Flunixin and an Amino
Acid Ester
Compositions containing a salt of flunixin and tryptophan
octanoate: 1.5 g of flunixin and 1.766 g of tryptophan octanoate
were weighed into a 10 mL volumetric flask. 0.5 mL of propylene
glycol was added to the flack and the flask filled to about 90% of
the volume with glycerol formal. The flask was then placed on a
shaker and shaken with occasional sonication over a period of about
30 min to provide a clear solution. The flask was then filled to
volume of 10 mL with glycerol formal. When 1 mL of the
pharmaceutical composition is injected into 5 mL of water, a
precipitate is observed to form.
Compositions containing a salt of flunixin and tryptophan
butanoate: 0.75 g of flunixin and 0.73 g of tryptophan butanoate
were weighed into a 5 mL volumetric flask. 0.25 mL of propylene
glycol was added to the flask and the flask filled to about 90% of
the volume with glycerol formal. The flask was then placed on a
shaker and shaken with occasional sonication over a period of about
30 min to provide a clear solution. The flask was then filled to
volume of 5 mL with glycerol formal. When 1 mL of the
pharmaceutical composition is injected into 5 mL of water, a
precipitate is observed to form.
A solution of fee flunixin (i.e., not as a salt) was also prepared
by weighing 1.5 g of flunixin into a 10 mL volumetric flask and
filling the flask to about 90% of the volume with
N-methylpyrrolidone. The flask was then placed on a shaker and
shaken with occasional sonication over a period of about 10 min to
provide a clear solution. The flask was then filled to volume a
volume of 10 mL with N-methylpyrrolidone. When 1 mL of the
pharmaceutical composition is injected into 5 mL of water, a
precipitate is observed to form.
In vitro release of flunixin from the flunixin containing
pharmaceutical compositions: 1 mL aliquots of each of the above
flunixin compositions were sealed in a dialysis bag (commercially
available from Pierce Biotechnology, Inc. of Rockford Ill.) and the
dialysis bag suspended in flasks containing 150 mL of phosphate
buffered saline at pH 7.4. When the dialysis bag is suspended into
the flask containing phosphate buffered saline, a precipitate was
observed to form in the dialysis bag. Aliquots of saline were then
removed at various intervals and the concentration of flunixin
determined using high pressure liquid chromatography (HPLC).
For HPLC analysis 100 .mu.L was injected on a Phenomenex Luna 5:M
phenyl-hexyl 100A, 250.times.4.6 mm analytical column operated at a
flow rate of 1.7 mL/min. The HPLC was interfaced to a UV detector
operated at 285 nm. The HPLC column was eluted using gradient
elution according to the following profile:
TABLE-US-00001 Time Percent Pump A Percent Pump B 0 30 70 10.5 85
15
wherein the solvent in pump A was 25 mM phosphate buffer at pH 2.4
and the solvent in pump B was acetonitrile. The total run time was
25 min. The serum concentration of flunixin was then determined by
comparing the area under the curve for the HPLC peak corresponding
to flunixin to a standard curve of peak areas v. known
concentrations of flunixin in phosphate-buffered saline. The
standard curve was prepared using the following concentrations of
flunixin 4, 2, 1, 0.5, and 0 g/mL.
FIG. 1 shows the percent of flunixin released as a function of time
for each of the flunixin formulations. (.tangle-solidup.)
represents the percent of flunixin released from the composition
containing the salt of flunixin and tryptophan octanoate,
(.box-solid.) represents the percent of flunixin released from the
composition containing the salt of flunixin and tryptophan
butanoate, and (.diamond-solid.) represents the percent of flunixin
released from the composition containing free flunixin dissolved in
N-methylpyrrolidone.
The results depicted in FIG. 1 show that the flunixin compositions
of the invention release flunixin into saline at a substantially
slower rate than a composition containing free flunixin. The
results also demonstrate that by varying the amino acid ester, the
rate of release of flunixin can be modulated. The data depicted in
FIG. 1 show that flunixin is released more slowly from tryptophan
octanoate than from tryptophan butanoate. Tryptophan octanoate is
more lipophilic than tryptophan butanoate.
Example 9.3
Administration of Flunixin to Dogs
Two dogs were injected with commercially available flunixin
(Banamine.RTM., commercially available from Schering-Plough Animal
Health, Omaha, Nebr.) at a dose of 8 mg/kg.
Four dogs were injected with the composition of Example 9.2
containing the salt of flunixin and tryptophan octanoate in
propylene glycol and glycerol formal at a dose of 8 mg/kg.
Blood was withdrawn from each dog at various time intervals and the
serum concentration of flunixin determined by the following
procedure:
(i) A Strata X-C 33 .mu.m Cation Mixed-Mode Polymer 30 mg/mL
cartridge was condition by washing with 1 mL of methanol and 1 mL
of deionized water using gravity flow;
(ii) 1 mL of serum acidified with 20 .mu.l of phosphoric acid was
applied to the conditioned cartridge;
(iii) The column was washed with 1 mL of 0.1%
H.sub.3PO.sub.4/H.sub.2O, 1 mL of acetonitrile, and 2 mL of
methanol;
(iv) The column was eluted with 4 mL ammonia in methanol (15% of 2M
NH.sub.4OH in methanol);
(v) The solvent was removed from the eluant using a stream of
nitrogen gas; and
(vi) The resulting residue was then reconstituted with 1 mL of
50:50 methanol/50 mM phosphate buffer at pH 2.3 and analyzed by
HPLC using the HPLC method described in Example 9.2.
FIG. 2 depicts the average serum concentration of flunixin as a
function of time for the two dogs administered Banamine.RTM..
FIG. 3 depicts the average serum concentration of flunixin as a
function of time for the four dogs administered the composition of
Example 9.2 containing the salt of flunixin and tryptophan
octanoate propylene glycol and glycerol formal.
The results depicted in FIG. 2 and FIG. 3 show that by using the
compositions of the invention it is possible to maintain an
effective serum level of flunixin for a longer length of time than
is possible using a commercially available formulations of flunixin
(Banamine.RTM., commercially available from Schering-Plough Animal
Health, Omaha, Nebr.).
Example 9.4
Preparation of N-acyl Amino Acids
Phenylalanine butyramide: 5 g of phenylalanine was added to 20 mL
of butyric anhydride and the resulting mixture heated to about
100.degree. C. for about 3 h. Excess butyric anhydride was then
removed under reduced pressure to provide a solid residue that was
recrystallized from ethanol to provide phenylalanine
butyramide.
Example 9.5
Compositions Comprising a Phosphorylated Nucleotide
Adenosine monophosphate (AMP) is used as a model for a
phosphorylated nucleotide.
Compositions containing a salt of AMP and isoleucine butyrate: 1.2
g of isoleucine butyrate and 1 g of AMP were weighed into a 10 mL
volumetric flask and the volumetric flask filled to about 90% of
the volume with glycerol formal. The flask was shaken to dissolve
the AMP isoleucine butyrate and then the flask was filled to volume
with glycerol formal. 1 eq. of a phosphorylated nucleotide such as
adefovir can be substituted for each eq. of AMP. 1 g of AMP alone,
i.e., in the absence of isoleucine butyrate, will not dissolve in
10 mL of glycerol formal.
Compositions containing a salt of AMP and isoleucine butyrate and a
salt of decanoic acid and isoleucine butyrate: 1 g of AMP, 0.99 g
of decanoic acid, and 2.4 g of isoleucine butyrate were weighed
into a 10 mL volumetric flask and the volumetric flask filled to
about 90% of the volume with glycerol formal. The flask was shaken
to dissolve the AMP, decanoic acid, and isoleucine butyrate and
then the flask was filled to volume with glycerol formal. 1 eq. of
a phosphorylated nucleotide such as adefovir can be substituted for
each eq. of AMP.
Compositions containing a salt of AMP and tyrosine butyrate: 0.682
g of tyrosine butyrate and 0.5 g of AMP were weighed into a 10 mL
volumetric flask and the volumetric flask filled to about 90% of
the volume with N-methylpyrrolidone. The flask was sonicated for
about 30 min to dissolve the AMP and tyrosine butyrate and then the
flask was filled to volume with N-methylpyrrolidone. 1 eq. of a
phosphorylated nucleotide such as adefovir can be substituted for
each eq. of AMP. 0.5 g of AMP alone, i.e., in the absence of
tyrosine butyrate, will not dissolve in 10 mL of N-methyl
pyrrolidone.
Compositions containing a salt of AMP and phenylalanine
dodecanoate: 1 g of phenylalanine dodecanoate and 0.347 g of AMP
were weighed into a 10 mL volumetric flask and the volumetric flask
filled to about 90% of the volume with N-methyl pyrrolidone. The
flask was sonicated for about 30 min to suspend the AMP and
phenylalanine dodecanoate and the flask was filled to volume with
N-methylpyrrolidone. The flask was then shaken to provide an
injectable composition of a suspension of AMP and phenylalanine
dodecanoate. 1 eq. of a phosphorylated nucleotide such as adefovir
can be substituted for each eq. of AMP.
Compositions containing a salt of AMP and 2.1 equivalents of the
ester made from lysine and a C.sub.16 straight chain alcohol (i.e.,
CH.sub.3(CH.sub.2).sub.14CH.sub.2--OH): 45 mg of AMP and 96 mg of
the lysine ester were suspended in about 2 mL of glycerol formal.
The resulting suspension was placed in a sonic bath and shaken and
to provide a clear solution. The volume of the solution was made up
to a volume of 3 mL. The resulting solution contains the salt of
AMP at a concentration of about 1.5% (w/v). When 1 mL of the
pharmaceutical composition is injected into 5 mL of water, a
precipitate is observed to form.
Compositions containing a salt of AMP and 2.1 equivalents of the
ester made from lysine and a C.sub.16 straight chain alcohol (i.e.,
CH.sub.3(CH.sub.2).sub.14CH.sub.2--OH): 150 mg of AMP and 320 mg of
the lysine ester were suspended in about 2 mL of glycerol formal.
The resulting suspension was placed in a sonic bath and shaken and
to provide a clear solution. The volume of the solution was made up
to a volume of 3 mL. The resulting solution contains the salt of
AMP at a concentration of about 5% (w/v). When 1 mL of the
pharmaceutical composition is injected into 5 mL of water, a
precipitate is observed to form.
Compositions containing a salt of AMP and 6.6 equivalents of the
ester made from lysine and a C.sub.16 straight chain alcohol (i.e.,
CH.sub.3(CH.sub.2).sub.14CH.sub.2--OH): 150 mg of AMP and 1.92 g of
the lysine ester were suspended in about 2 mL of glycerol formal.
The resulting suspension was placed in a sonic bath and shaken and
to provide a clear solution. The volume of the solution was made up
to a volume of 3 mL. The resulting solution contains the salt of
AMP at a concentration of about 5% (w/v). When 1 mL of the
pharmaceutical composition is injected into 5 mL of water, a
precipitate is observed to form.
Example 9.6
Pharmaceutical Composition Comprising Isoleucine Butyrate, Lauric
Acid, and Terbinafine
A: Terbinafine (5 g), lauric acid (7.56 g), and isoleucine butyrate
(3.54 g) were suspended in about 15 mL of glycerol formal in a 25
mL volumetric flask. The resulting suspension was then sonicated to
provide a clear solution. Propylene glycol (1.5 mL) was added and
the resulting solution mixed well. The volumetric flask was then
filled to a volume of 25 mL with glycerol formal to provide a clear
solution. The resulting pharmaceutical composition contains 20%
(w/v) terbinafine as the lauric acid salt. The pharmaceutical
composition also contains the salt formed between lauric acid and
isoleucine butyrate. When 1 mL of the pharmaceutical composition is
injected into 5 mL of water, a precipitate is observed to form.
B: As a comparison, another pharmaceutical composition was prepared
that does not include the salt formed between lauric acid and
isoleucine butyrate. The composition was prepared by suspending
terbinafine (5 g) and lauric acid (1.1 eq.) in about 15 mL of
glycerol formal in a 25 mL volumetric flask and sonicating the
resulting solution to provide a clear solution. Propylene glycol
(1.5 mL) was added and the resulting solution mixed well. The
volumetric flask was then filled to a volume of 25 mL with glycerol
formal to provide a clear solution. The resulting pharmaceutical
composition contains 20% (w/v) terbinafine as the lauric acid salt.
When 1 mL of the pharmaceutical composition is injected into 5 mL
of water, a precipitate is observed to form.
Example 9.7
Administration of Terbinafine to Dogs
Three dogs (dogs A, B, and C) were administered the pharmaceutical
composition of Example 9.6 A at a dose of 20 mg/kg by subcutaneous
injection in the neck.
Three other dogs (dogs D, E, and F) were administered the
pharmaceutical composition of Example 9.6 B at a dose of 20 mg/kg
by subcutaneous injection in the neck.
Three other dogs (dogs G, H, and I) were orally administered a
commercially available 250 mg terbinafine tablet (commercially
available as Lamisil Tablets.RTM. from Novartis Pharmaceutical
Corporation of New Jersey) once per day for 6 days.
Serum samples were obtained from each dog at 0, 1, 12, 24, 48, 72,
and 168 hours and subjected to solid phase extraction, described
below, and then analyzed by HPLC using the HPLC method described
below. Also, 7 days after injection, a skin biopsy was taken of the
right, left, and center of the dorsoscapular region of each dog and
the tissue analyzed for terbinafine as described below. For the
dogs administered terbinafine by injection, the injection site was
monitored by a veterinarian for adverse reaction.
Tissue Preparation: 1. Mince tissue thoroughly. 2. Place about 5 mg
of minced tissue in a vial and add 10 mL of methanol. 3. Add 200
.mu.L of phosphoric acid to the resulting methanol solution. 4.
Cool the methanol solution in an ice bath to minimize heating and
then homogenize the methanol solution for about 1 min. 5.
Ultrasonicate the methanol solution for about 20 seconds. 6.
Homogenize the methanol solution for about 1 min. 7. Ultrasonicate
the methanol solution for about 20 seconds. 8. Centrifuge the
methanol solution at about 4.degree. C. and about 8250 rcf for
about 30 min. 9. Decant the resulting supernatant into a separate
vial to avoid mixing pellet back into the supernatant during solid
phase extraction. 10. Perform solid phase extraction as described
below on the supernatant.
Solid Phase Extraction of Serum or Supernatant: 1. Condition a
Strata 30 mg/l mL X-C cartridge (commercially available from
Mallinckrodt Baker, Inc. of Phillipsburg, N.J.) with 1 mL of
methanol and 2 mL of deionized water using gravity flow. 2. Apply 1
mL of serum (or supernatant) acidified with 20 .mu.L of phosphoric
acid to the conditioned cartridge. 3. Wash the cartridge with 1 mL
0.1% H.sub.3PO.sub.4/H.sub.2O, 1 mL acetonitrile, and 1 mL of
methanol. 4. Elute the cartridge with 1850 .mu.L of 15%
diethylamine in methanol into a 2 mL volumetric flask. 5. Fill the
volumetric flask to 2 mL with 15% diethylamine. 6. Add 1000 .mu.L
of 50% phosphoric acid to the 2 mL volumetric flask and vortex the
resulting mixture. 7. Filter the resulting solution into a vial. 8.
Analyze the resulting solution for terbinafine using the HPLC
method described below.
Analysis of Terbinafine by HPLC: Column: Phenomenex Lunar.RTM.
5.mu., C8, 100 .ANG., 250 mm.times.4.6 mm (commercially available
from Phenomenex of Torrance, Calif.). Mobile Phase: 40% 25 mM
Phosphate Buffer pH 2.4 60% Methanol Elution Profile: Isocratic.
Detection: UV, 223 nm Temperature: Ambient Injection: 100 .mu.L Run
Time: 20 min, isocratic. Flow rate: 1 mL/min Limit of detection:
about 8 ng/mL Limit of quantitation: about 75 ng/mL
The concentration of terbinafine was determined by comparing the
area under the curve for the HPLC peak corresponding to terbinafine
to a standard curve of peak area v. known concentrations of
terbinafine. The standard curve was obtained by: 1. Prepare a
standard stock solution at a concentration of 1 mg/mL of
terbinafine in methanol by weighing 100 mg of terbinafine into a
100 mL volumetric flask and diluting to volume. 2. Prepare the
following serum spiking solutions: Solution A: 400 .mu.L standard
stock solution+600 .mu.L methanol=400 .mu.g/mL of terbinafine
Solution B: 200 .mu.L standard stock solution+800 .mu.L
methanol=200 .mu.g/mL of terbinafine Solution C: 100 .mu.L standard
stock solution+900 .mu.L methanol=100 .mu.g/mL of terbinafine
Solution D: 50 .mu.L standard stock solution+950 .mu.L methanol=50
.mu.g/mL of terbinafine Solution E: 10 .mu.L standard stock
solution+990 .mu.L methanol=10 .mu.g/mL of terbinafine Solution F:
0 .mu.L standard stock solution+1000 .mu.L methanol=0 .mu.g/mL of
terbinafine 3. Prepare the following standard serum solutions: a.
15 .mu.L Solution A+1485 .mu.L serum=4 .mu.g/mL of terbinafine. b.
15 .mu.L Solution B+1485 .mu.L serum=2 .mu.g/mL of terbinafine. c.
15 .mu.L Solution C+1485 .mu.L serum=1 .mu.g/mL of terbinafine. d.
15 .mu.L Solution D+1485 .mu.L serum=0.5 .mu.g/mL of terbinafine.
e. 15 .mu.L Solution E+1485 .mu.L serum=0.1 .mu.g/mL of
terbinafine. f. 15 .mu.L Solution E+1485 .mu.L serum=0 .mu.g/mL of
terbinafine.
Each of the above standard serum solutions is analyzed using the
HPLC method described above to generate a standard curve. The
following peak areas were obtained for each of the standard serum
solutions:
TABLE-US-00002 Terbinafine Concentration (.mu.g/mL) HPLC Area 0.1
59.92624 0.5 279.6904 1.0 566.0115 2.0 1073.03 4.0 2214.295
A positive control (to demonstrate that the analysis is capable of
detecting terbinafine) is prepared by adding 1 mL of 15%
diethylamine in methanol to a 2 mL volumetric flask followed by 10
.mu.L of Solution A and filling the volumetric flask to volume with
15% diethylamine in methanol. To the resulting solution is then
added 1 mL of 50% phosphoric acid and the resulting solution mixed
using a vortex mixer. The resulting positive control has a
terbinafine concentration of 4 .mu.g/mL. A positive control having
a concentration of 0.5 .mu.g/mL can be made following the same
procedure except using 10 .mu.L of Solution D.
A negative control (to demonstrate that the no other compounds
co-elute with terbinafine) is prepared by mixing 2 mL of 15%
diethylamine in methanol with 1 mL of 50% phosphoric acid in a test
tube and mixing the resulting solution using a vortex mixer for
about 10 sec.
The average concentration of terbinafine in the serum of each group
of dogs was determined as described above and is provided below in
Table I:
TABLE-US-00003 TABLE I Average Serum Concentration of Terbinafine
Time (hours) Dogs A, B, and C Dogs D, E, and F Dogs G, H, and I 0
0.00 0.00 0.00 1 0.02 0.01 2.36 12 0.12 0.02 0.08 24 0.27 0.02 0.46
48 0.05 0.02 0.25 72 0.17 0.01 0.85 168 0.05 0.12 3.23
It is known that terbinafine can be toxic at high systemic and
tissue concentrations. The results show that administering a single
injection of the pharmaceutical composition of the invention
provides a serum level of terbinafine over a period of 7 days that
is less than when terbinafine is orally administered once daily as
a commercially available tablet. The pharmaceutical compositions of
the invention, however, provide a serum level of terbinafine that
is physiologically relevant for the intended therapeutic
effect.
The pharmaceutical composition of the invention containing
terbinafine as the lauric acid salt and the salt formed between
lauric acid and isoleucine butyrate provides a lower level of
terbinafine in the serum than terbinafine administered orally once
per day for 6 days as a 250 mg tablet. Accordingly, administering
terbinafine using the pharmaceutical composition of the invention
is less toxic than orally administered terbinafine.
Visually inspection of the injection site for the dogs administered
terbinafine by injection i.e., dogs A, B, and C and dogs D, E, and
F, by a veterinarian indicated that the dogs administered the
pharmaceutical composition of Example 9.6 A containing terbinafine
as the lauric acid salt and also containing the salt formed between
lauric acid and isoleucine butyrate (i.e., dogs A, B, and C) showed
less swelling and irritation at the injection site than the dogs
that were administered the pharmaceutical composition of Example
9.6 B containing terbinafine as the lauric acid salt (i.e., dogs D,
E, and F). These results show that the pharmaceutical composition
containing the salt formed between lauric acid and isoleucine
butyrate in combination with terbinafine as the lauric acid salt is
less irritating than a pharmaceutical composition that contains
only terbinafine as the lauric acid salt when administered by
subcutaneous injection.
The tissue concentration of terbinafine was also determined for
each of the dogs and is provided below in Table II.
TABLE-US-00004 TABLE II Tissue Concentration of Terbinafine in
Tissue Obtained From the Right, Left, and Center of the
Dorsoscapular Region (.mu.g/g) Dog Center Left Right A 31.34 --
222.5.sup.a B 19.74 27.43 38.40 C 20.17 15.38 28.14 Average 24.72
21.40 96.36 (33.27).sup.b D 29.54 26.64 20.08 E 16.42 19.26 141.61
F 45.43 31.48 34.82 Average 30.49 25.79 65.50 G 97.24 117.52 108.23
H 121.57 73.68 72.80 I 46.79 33.47 38.11 Average 88.53 74.89 73.05
.sup.aValue appears to be in error, although the source of the
error is unclear. .sup.bIf the value of 222.5 .mu.g/g for dog A is
eliminated, the average value is 33.27 .mu.g/g.
As discussed above, it is known that terbinafine can be toxic at
high systemic and tissue concentrations. The results show that
administering a single injection of the pharmaceutical composition
of the invention provides a tissue concentration of terbinafine
over a period of 7 days that is less than when terbinafine is
orally administered once daily as a commercially available tablet.
The pharmaceutical compositions of the invention, however, provide
a tissue concentration of terbinafine that is physiologically
relevant for the intended therapeutic effect.
The present invention is not to be limited in scope by the specific
embodiments disclosed in the examples which are intended as
illustrations of a few aspects of the invention and any embodiments
that are functionally equivalent are within the scope of this
invention. Indeed, various modifications of the invention in
addition to those shown and described herein will become apparent
to those skilled in the art and are intended to fall within the
scope of the appended claims.
A number of references have been cited, the entire disclosure of
which are incorporated herein by reference.
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